RecruitingPhase 2NCT06770582

Testing the Addition of the Immunotherapy Drug, Pembrolizumab, to Radiation Therapy Compared to the Usual Chemotherapy Treatment During Radiation Therapy for Bladder Cancer, PARRC Trial

Randomized Phase II Trial of Pembrolizumab and Radiation vs. Radiation and Concurrent Chemotherapy for High-Grade T1 Bladder Cancer (PARRC Trial)

Sponsor

National Cancer Institute (NCI)

Enrollment

160 participants

Start Date

Jun 3, 2025

Study Type

INTERVENTIONAL

Conditions

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

Summary

This phase II trial compares the use of pembrolizumab and radiation therapy to chemotherapy with cisplatin, gemcitabine, 5-fluorouracil or mitomycin-C and radiation therapy for the treatment of non-muscle invasive bladder cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as cisplatin, gemcitabine, 5-fluorouracil or mitomycin-C, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving pembrolizumab with radiation may kill more tumor cells than chemotherapy with radiation therapy in patients with non-muscle invasive bladder cancer.

Eligibility

Min Age: 18 Years

Inclusion Criteria41

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

Interventions

PROCEDUREBiospecimen Collection

Undergo blood and urine sample collection

DRUGCisplatin

Given IV

PROCEDUREComputed Tomography

Undergo CT

DRUGFluorouracil

Given IV

DRUGGemcitabine

Given IV

PROCEDUREMagnetic Resonance Imaging

Undergo MRI

DRUGMitomycin

Given IV

BIOLOGICALPembrolizumab

Given IV

OTHERQuestionnaire Administration

Ancillary studies

RADIATIONRadiation Therapy

Undergo radiation therapy

Locations(113)

AIS Cancer Center at San Joaquin Community Hospital

Bakersfield, California, United States

Los Angeles General Medical Center

Los Angeles, California, United States

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

Shaw Cancer Center

Edwards, Colorado, United States

Helen F Graham Cancer Center

Newark, Delaware, United States

Medical Oncology Hematology Consultants PA

Newark, Delaware, United States

UF Health Cancer Institute - Gainesville

Gainesville, Florida, United States

Mount Sinai Medical Center

Miami Beach, Florida, United States

Grady Health System