Phase Ib/II Study of Enfortumab Vedotin and Pembrolizumab Combined With Radiotherapy as a Bladder-Sparing Trimodality Therapy in Muscle Invasive Bladder Cancer
This phase Ib/II trial studies the side effects, best dose, and effectiveness of enfortumab vedotin (EV) in combination with pembrolizumab and radiation therapy for treating patients with muscle invasive bladder cancer. Standard of care treatment for muscle invasive bladder cancer is chemotherapy, to shrink the tumor before the main treatment is given (neoadjuvant), followed by surgery to remove all of the bladder as well as nearby tissues and organs (radical cystectomy). In cases where patients are not candidates for the standard of care approach or prefer a bladder sparing option, tri-modality therapy with transurethral resection of bladder tumor (TURBT) followed by combined chemotherapy and radiation therapy is used. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of tumor cells. Enfortumab attaches to a protein called nectin-4 on tumor cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. 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. Intensity-modulated radiation therapy is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor. Giving enfortumab vedotin with pembrolizumab and radiation therapy may work better in treating patients with muscle invasive bladder cancer.
• Biopsy-confirmed muscle-invasive bladder cancer (cT2,T3,T4a). (Note: Tissue samples are required.) (Participants with cT3/T4a staged disease will be capped at 25% of patients treated at RP2D).
• Urothelial-predominant histology. Mixed histologies other than small cell/neuroendocrine are allowed as long as some urothelial histology is present. Neuroendocrine histology of any component and pure variant (non-urothelial) histology tumors will be excluded. (Patients with \< 50% urothelial histology will be capped at 25% of patients treated at RP2D).
• Must be judged by the investigator to be ineligible for radical cystectomy or electing not to undergo radical cystectomy.
• Must be eligible for and agree to receive bladder irradiation as determined by the treating investigator.
• Must have a TURBT within 8 weeks of combination treatment start with viable tumor content. If no viable tumor content is present on TURBT, the patient will be replaced in the study.
• Patients who have autoimmune disease will be evaluated on a case-by-case basis and can only enroll so long as participants are not on active immunosuppression with a corticoid steroid allowance exceeding 10mg of prednisone or equivalent per day.
• Age \>= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status \<= 1.
• Absolute neutrophil count ≥ 1,500/microliter (mcL).
• Platelets \>= 100,000/mcL.
• Hemoglobin \>= 9.0 g/dL or ≥ 5.6 mmol/L.
• \* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Total bilirubin \<= 1.5 × upper limit of normal, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) \<= 2.5 X institutional upper limit of normal.
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) \<= 2.5 X institutional upper limit of normal.
• Creatinine clearance glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2, calculated by Cockcroft-Gault or measured using 24-hour creatinine clearance.
• International normalized ratio (INR) OR prothrombin time (PT) \<= 1.5 × upper limit of normal (ULN).
• \* If participant is receiving anticoagulant therapy, as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants, participant is eligible.
• Activated partial thromboplastin time (aPTT) \<= 1.5 × ULN.
• \* If participant is receiving anticoagulant therapy, as long as PT or aPTT is within therapeutic range of intended use of anticoagulants, participant is eligible.
• Ability to understand and the willingness to sign a written informed consent document.
• Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Participants who are hepatitis B virus surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) anti-viral therapy for at least 4-weeks, and have undetectable HBV viral load prior to randomization. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
• \* Note: Hepatitis B screening tests are not required unless patients have a known history of HBV infection.
• Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.
• \* Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to cycle 1 day 1.
• Women of child-bearing potential and men with sexual partners of childbearing potential must agree to use adequate contraception for the duration of study participation. Enfortumab vedotin (EV) may cause fetal harm. Women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. Men with female partners who are women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Acceptable methods include barrier method, hormonal method, as well as intrauterine devices
• Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 8 weeks after last administration of study treatment.