University of Kansas Medical Center

Conditions

• Non-Muscle Invasive Bladder Urothelial Carcinoma
• Recurrent Non-Muscle Invasive Bladder Urothelial Carcinoma
• Stage I Bladder Cancer AJCC v8

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Pathologically (histologically) proven diagnosis of T1 high-grade non-muscle
invasive urothelial carcinoma of the bladder without radiographic evidence of
regional nodal disease or metastatic disease (N0, M0) on CT, MRI, or positron
emission tomography (PET)/CT scan who would otherwise be treated with cystectomy
off-trial. Patients should have cystectomy recommended disease but do not need to be
medically operable for a cystectomy to be eligible for the trial.

- NOTE: Patients with nodal disease ≥ 1 cm on short-axis or with suspicious nodes
that are PET-avid of any size are not eligible

- High grade T1 disease history that must meet at least ONE of the three criteria
below:

- Histologically confirmed recurrence with high-grade T1 urothelial carcinoma
(+/- focal carcinoma in situ [CIS]) in the bladder following initial
transurethral resection of bladder tumor (TURBT) and at least one induction
course of intravesical therapy. Adequate induction course is defined as ≥ 5
doses of intravesical Bacillus Calmette-Guerin (BCG) or intravesical
chemotherapy when BCG is not available.

- T1 with pathologic high-risk features (lymphovascular invasion [LVI] or variant
histology of micropapillary, sarcomatoid, or plasmacytoid features) post
initial TURBT. (No prior intravesical therapy required)

- Persistent high-grade T1 urothelial carcinoma at repeat TURBT (+/- focal CIS)
in the bladder. (No prior intravesical therapy required)

- Restaging TURBT must be performed and must meet ALL of the following criteria below:

- If there is absence of muscularis propria in the initial TURBT, there must be
uninvolved muscularis propria in the restaging TURBT.

- All grossly visible papillary tumors must be removed

- Note: If the restaging TURBT is performed outside of the enrolling
institution, an office cystoscopy should be performed by a Urologist who
will be following the patient as part of the clinical trial

- No pure squamous cell carcinoma or adenocarcinoma of the bladder

- No neuroendocrine (small or large cell) features

- No diffuse carcinoma in situ determined on cystoscopy and biopsy (i.e. extensive
carcinoma in situ that is not just tumor-associated CIS in the opinion of the site
investigator)

- No prostatic urethral involvement

- Age ≥ 18

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Negative urine or serum pregnancy test (in persons of childbearing potential) within
14 days prior to registration. Childbearing potential is defined as any person who
has experienced menarche and who has not undergone surgical sterilization
(hysterectomy or bilateral oophorectomy), tubal ligation or who is not
postmenopausal

- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3

- Platelets ≥ 100,000 cells/mm^3

- Hemoglobin ≥ 9 g/dl (Note: The use of transfusion or other intervention to achieve
hemoglobin [Hgb] ≥ 9 g/dl is acceptable)

- Adequate renal function defined as creatinine clearance (CrCL) of ≥ 30 mL/min by the
Cockcroft-Gault formula, ≤ 1.5 × upper limit of normal (ULN) or creatinine levels >
1.5 × institutional ULN

- Total bilirubin ≤ institutional upper limit of normal (ULN) (Not applicable to
patients with known Gilbert's syndrome)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3
x institutional ULN

- All adverse events of their most recent therapy/intervention must have resolved to <
grade 3 or returned to baseline prior to registration

- No history of pelvic radiation therapy

- No prior systemic chemotherapy or immunotherapy for urothelial carcinoma. Prior
treatment with local intravesical therapy including BCG or chemotherapy is allowed

- No prior treatment with anti-PD-1, anti PD-L1, anti PD-L2 or anti-CTLA4 antibody or
any other antibody or drug targeting T-cell co-stimulation

- No live vaccine administered within 30 days of registration. All non live vaccines
(including the coronavirus disease [COVID] vaccine) are allowed at any time during
the study. Timing should minimize confusion with drug-related toxicities where
possible

- Patients must have recovered from acute cardiac illness

- New York Heart Association Functional Classification II or better (New York Heart
Association [NYHA] Functional Classification III/IV are not eligible) (Note:
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.)

- No active infection requiring IV antibiotics

- No active autoimmune disease that required systemic treatment in the past 2 years
(i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered
a form of systemic treatment

- No history of idiopathic pulmonary fibrosis, organizing pneumonia, (non-infectious)
pneumonitis that required steroids or current pneumonitis

- No history of allogeneic bone marrow transplant or prior solid organ transplant

- No active tuberculosis

- No evidence of hydronephrosis

- No history of upper tract urothelial carcinoma within 24 months of registration

- No patients with a prior diagnosis of prostate cancer who have not received
definitive treatment for their prostate cancer (e.g. on active surveillance)

- 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

- No glucocorticoids except physiologic doses are allowed. The use of doses of
corticosteroids (defined as 10 mg prednisone or equivalent) is acceptable

- No history of allergic reaction to the drug excipients

Recruiting Locations

Study Contact

Detailed Description

PRIMARY OBJECTIVE: I. To compare bladder-intact event-free survival. SECONDARY OBJECTIVES: I. To assess complete response by cystoscopy at 6 months. II. To assess disease-free survival. III. To assess local-regional control. IV. To assess metastasis-free survival. V. To assess overall survival. VI. To assess quality of life using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Bladder Cancer Index at 18 months. VII. To assess Common Terminology Criteria for Adverse Events (CTCAE) adverse events (both acute and late). EXPLORATORY OBJECTIVES: I. To assess fatigue using the Patient Reported Outcomes Measurement Information System Fatigue-4A (PROMIS-Fatigue-4a). II. To assess quality adjusted survival using European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L). III. To assess cumulative quality of life using EORTC QLC-C30 and Bladder Cancer Index at 24 months. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive one of the following chemotherapy regimens per physicians choice: 1) cisplatin intravenously (IV) once per week for 4 weeks, 2) gemcitabine IV on days 1, 4, 8, 11, 15, 18, 22, and 25, or 3) mitomycin IV on day 1 and 5-fluorouracil IV continuously over 120 hours on days 1-5 and 16-20. Patients receiving cisplatin or gemcitabine continue chemotherapy for 6 weeks if they are receiving radiation according to the standard hypofractionated radiation schedule. Starting on day 1, patients also receive radiation therapy for 20, 32, or 36 treatments over 4-7 weeks. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT)/magnetic resonance imaging (MRI) and blood sample collection throughout the study. Patients may also undergo optional urine sample collection on study. ARM 2: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for 9 cycles in the absence of disease progression or unacceptable toxicity. Starting on day 1, patients also receive radiation therapy for 20, 32, or 36 treatments over 4-7 weeks. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo CT/MRI and blood sample collection throughout the study. Patients may also undergo optional urine sample collection on study. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years and then annually for 5 years.