Clinical Trial 23976

• Overview

  Study Title:

  Single Arm Phase II Study of Bladder Preservation with Immunoradiotherapy After a Clinically Meaningful Response to Neoadjuvant Therapy in Patients with Muscle Invasive Bladder Cancer (BRIGHT)

  Summary:

  This phase II trial tests the effect of giving pembrolizumab in combination with radiation therapy after chemotherapy in preventing surgery to remove the bladder in patients with muscle invasive bladder cancer. Standard of care therapy includes chemotherapy before surgery (neoadjuvant) to shrink or get rid of the tumor. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Photon beam radiation therapy is a type of radiation therapy that uses x-rays or gamma rays that come from a special machine called a linear accelerator. The radiation dose is delivered at the surface of the body and goes into the tumor and through the body. Giving pembrolizumab in combination with radiation therapy after neoadjuvant chemotherapy may help prevent surgical removal of the bladder in patients with muscle invasive bladder cancer.

  Objective:

  Primary Objective * To evaluate whether 3-year bladder intact event-free survival (BI-EFS) is at least 70% in participants with clinically T0-clinically T1 without multifocal CIS following neoadjuvant therapy (NAT) for muscle-invasive bladder cancer (MIBC) who receive radiotherapy (RT) + pembrolizumab (MK-3475). Secondary Objectives * To estimate BI-EFS in participants who receive RT + pembrolizumab (MK-3475). * To estimate local muscle invasive recurrence-free survival in participants who receive RT+ pembrolizumab (MK-3475). * To estimate the metastasis-free survival (MFS) in participants who receive RT+ pembrolizumab (MK-3475). * To estimate the overall survival (OS) in participants who receive RT + pembrolizumab (MK-3475). * To estimate the rate of salvage cystectomy in participants who receive RT+ pembrolizumab (MK-3475). * To evaluate the frequency and severity of toxicities in participants who receive RT + pembrolizumab (MK-3475).

• Treatments

  Therapies:

  Immunotherapy; Radiotherapy

  Medications:

  Pembrolizumab (Keytruda); Radiotherapy ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Participants must have histologic evidence of cT2-T4aN0M0 muscle invasive urothelial carcinoma of the bladder within 180 days prior to starting neoadjuvant therapy (NAT)
  • Participants must have had CT chest/abdomen/pelvis (C/A/P), MRI C/A/P or PET within 60 days prior to starting NAT to determine cT2-T4aN0M0
  • Participants must have undergone TURBT with biopsy of areas of prior disease and systematic biopsies (left and right lateral, dome, posterior wall and trigone) and radiologic staging showing clinically T0-T1 disease within 60 days after the last dose of NAT
  • Participants must have imaging of the chest, abdomen, and pelvis performed using CT or MRI preferably with contrast. Fludeoxyglucose F-18 (FDG) PET-CT can also be used for staging. If FDG PET-CT is used, then it is at the discretion of the investigator if they want to additionally obtain diagnostic CT or MRI with contrast within 60 days after the last dose of NAT
  • Participants with lymph nodes ≥ 1.0 cm in the shortest cross-sectional diameter on imaging (CT or MRI of abdomen and pelvis) after completion of NAT must have a PET-CT within 70 days prior to registration. A biopsy in the setting of negative PET-CT is not required unless there is strong clinical suspicion for nodal involvement with tumor. Participants with a positive PET are deemed ineligible unless a biopsy is performed and shows no evidence of tumor involvement
  • Participants must not have evidence of ≥ T2, N1-3 or metastatic disease after NAT
  • Participants must not have the presence of small cell, neuroendocrine carcinoma, plasmacytoid variants on any pathology
  • Participants must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder within 24 months prior to registration except Ta/T1/carcinoma in situ (CIS) of the upper urinary tract, including renal pelvis or ureter if the participant underwent complete nephroureterectomy
  • Participants must have received at least 3 and no more than 6 cycles of National Comprehensive Cancer Network (NCCN) guideline concordant NAT for MIBC
  • Participants must not have had prior pelvic radiotherapy
  • Participants must not have had anti-PD-1, anti PD-L1, anti PD-L2 or anti-CTLA4 antibody, any other antibody or drug targeting T-cell co-stimulation, enfortumab vedotin, or any other drug targeting nectin-4
  • Participants must not have received a live attenuated vaccination within 28 days prior to registration
  • Participants with conditions requiring immunosuppressive doses of steroids (> 10 mg/day of prednisone or equivalent) or other immunosuppressive medications must not be taking steroids at time of trial registration
  • Participants must be ≥ 18 years old at the time of registration
  • Participants must have Zubrod performance status of 0-2
  • Participants must have a complete medical history and physical exam within 28 days prior to registration
  • Leukocytes ≥ 3 x 10^3/uL (within 28 days prior to registration)
  • Absolute neutrophil count ≥ 1.5 x 10^3/uL (within 28 days prior to registration)
  • Platelets ≥ 100 x 10^3/uL (within 28 days prior to registration)
  • Total bilirubin ≤ institutional upper limit of normal (ULN) unless history of Gilbert's disease (within 28 days prior to registration)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x institutional ULN (within 28 days prior to registration)
  • Participants must have a creatinine ≤ the institutional (I)ULN OR measured OR calculated creatinine clearance ≥ 40 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 3 days prior to registration
  • Additional protocol defined inclusion criteria may apply

• Exclusion Criteria

  Key Exclusion Criteria:
  • Not meeting the inclusion criteria.

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