PRIMARY OBJECTIVES:
I. To compare the ctDNA clearance proportion (i.e., ctDNA positive \[+\] --\> ctDNA negative \[-\]) at 12 weeks in patients enrolled in Cohort A treated with adjuvant nivolumab versus nivolumab + relatlimab (phase 2 portion).
II. To compare overall survival in patients enrolled in Cohort A treated with adjuvant nivolumab versus nivolumab + relatlimab (phase 3 portion).
III. To compare disease-free survival in patients enrolled in Cohort B randomized to immediate treatment with nivolumab to those randomized to surveillance with subsequent treatment with nivolumab only upon converting to ctDNA(+)
SECONDARY OBJECTIVES:
I. To compare disease-free survival in patients enrolled in Cohort A treated with adjuvant nivolumab versus nivolumab + relatlimab.
II. To define the association between ctDNA clearance and disease-free survival and overall survival for Cohort A patients.
III. To compare overall survival in patients enrolled in Cohort B randomized to immediate treatment with nivolumab to those randomized to surveillance with subsequent treatment with nivolumab only upon converting to ctDNA(+).
IV. To determine the lead time from a ctDNA(+) assay to radiographic recurrence in patients initially ctDNA(-) post-definitive surgery enrolled in Cohort B.
V. To estimate the proportion of Cohort B patients on Arm 4 who become ctDNA(+) and receive nivolumab.
VI. To compare the cumulative incidence of Cohort B patients who become ctDNA(+) between Arms 3 and 4.
VII. To determine the safety of adjuvant nivolumab plus relatlimab.
EXPLORATORY OBJECTIVES:
I. To explore the kinetics of quantitative ctDNA levels (mean number of tumor molecules observed per mL of plasma or MTM/ml) over time and the association between ctDNA kinetics and time-to-event outcomes.
II. To estimate the costs and value of care in patients with a ctDNA(+) assay post-cystectomy treated with adjuvant nivolumab versus nivolumab + relatlimab.
III. To estimate the costs and value of care in patients with a ctDNA(-) assay post-cystectomy treated with adjuvant nivolumab versus surveillance with subsequent treatment with nivolumab at the time of conversion to ctDNA(+).
QUALITY OF LIFE OBJECTIVES:
I. Within each cohort, to compare quality-adjusted survival among randomized arms using European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L).
II. Within Cohort B, to compare overall quality of life (QOL) as measured by the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) between baseline and 42 months (calculated as the area under the curve) among randomized arms.
III. Within each cohort, to compare overall QOL as measured by the EORTC QLQ-C30 at each time point among randomized arms.
IV. Within each cohort, to compare bladder cancer-specific QOL as measured by the EORTC Bladder Cancer Muscle-Invasive 30 Questionnaire (QLQ-BLM30) at each time point among randomized arms.
V. Within each cohort, to compare patient-reported fatigue as measured by Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue at each time point among randomized arms.
VI. Within each cohort, to compare patient-reported fear of cancer recurrence as measured by the Fear of Cancer Recurrence Inventory (FCRI)-Short Form at each time point among randomized arms.
OUTLINE: Patients are assigned to 1 of 2 cohorts based on ctDNA results.
COHORT A: Patients who are ctDNA(+) are randomized to 1 of 2 arms:
ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of tissue during screening and collection of blood throughout the trial. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans throughout the trial.
ARM II: Patients receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of tissue during screening and collection of blood throughout the trial. Patients also undergo CT or MRI scans throughout the trial.
COHORT B: Patients who are ctDNA(-) are randomized to 1 of 2 arms:
ARM III: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of tissue during screening and collection of blood throughout the trial. Patients also undergo CT or MRI scans throughout the trial.
ARM IV: Patients undergo ctDNA surveillance consisting of collection of tissue and blood during screening and collection of blood only on study and during follow up. Patients who convert to ctDNA(+) during surveillance then receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans throughout the trial.
After completion of study treatment, patients are followed up at weeks 60, 72, 84, 96, 120, 144, 196, and 248.
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.