Researchers are looking for new ways to treat people with high-risk muscle-invasive urothelial carcinoma (MIUC). Urothelial carcinoma is a type of bladder cancer that begins in cells that line the inside of the bladder and other parts of the urinary tract, such as part of the kidneys, ureters, and urethra. People with MIUC usually have chemotherapy before surgery, then surgery to remove the cancer. Chemotherapy is a type of medicine to destroy cancer cells or stop them from growing. After surgery, some people receive more treatment to prevent cancer from returning. Pembrolizumab is an immunotherapy, which is a treatment that helps the immune system fight cancer. Enfortumab vedotin (EV) is an antibody drug conjugate (ADC). An ADC attaches to a protein on cancer cells and delivers treatment to destroy those cells. Researchers want to learn if giving intismeran autogene (the study treatment) with pembrolizumab can prevent MIUC from returning after surgery. Intismeran autogene (also called mRNA-4157) is designed to treat each person's cancer by helping the person's immune system identify and kill cancer cells based on certain proteins found on those cancer cells.

The goals of this study are to learn if people who receive intismeran autogene and pembrolizumab are alive and cancer free longer than those who receive placebo and pembrolizumab, and to learn about the safety of intismeran autogene, pembrolizumab, and EV, and if people tolerate them.

Enrollment of participants into the Phase 1 Perioperative Cohort of this study is planned to start in approximately April of 2025.

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

• Has a histological diagnosis of urothelial carcinoma (UC)
• Must provide blood samples per protocol, to enable intismeran autogene production, and circulating tumor deoxyribonucleic acid testing
• Has an Eastern Cooperative Oncology Group performance status of 0 to 2 assessed within 7 days before randomization
• Must provide a formalin-fixed paraffin-embedded tumor tissue sample for next generation sequencing

Adjuvant Cohort:

• Has MIUC
• Has high-risk pathologic disease after radical resection
• For participants who have not received cisplatin-based neoadjuvant chemotherapy, are ineligible to receive cisplatin according to protocol pre-defined criteria

Perioperative Cohort:

• Has MIBC
• Is deemed eligible for RC and PLND and agrees to undergo curative intent standard RC and PLND and neoadjuvant and adjuvant treatment per protocol
• Is ineligible to receive cisplatin according to protocol pre-defined criteria

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Has known additional malignancy that is progressing or has required active treatment ≤3 years prior to study randomization
• Has current pneumonitis/interstitial lung disease
• Has active infection requiring systemic therapy
• Has active hepatitis B and hepatitis C virus infection

Adjuvant Cohort:

• Has received prior systemic anticancer therapy
• Has received prior neoadjuvant therapy, with the exception of neoadjuvant cisplatin-based chemotherapy for MIUC
• Has severe hypersensitivity to either intismeran autogene or pembrolizumab (MK-3475) and/or any of their excipients

Perioperative Cohort:

• Has received any prior systemic treatment, cancer vaccine treatment, chemoradiation, and/or radiation therapy treatment for MIBC
• Has severe hypersensitivity to either intismeran autogene, pembrolizumab, or EV and/or any of their excipients
• Has ongoing sensory or motor neuropathy
• Has active keratitis or corneal ulcerations

https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

The Phase 2 Adjuvant Cohort of study will be conducted as a double-blind study under in-house blinding procedures. Intismeran autogene and placebo will be prepared and dispensed by unblinded pharmacists and administered in a blinded fashion by blinded personnel. The participants and the investigators who are involved in the study intervention administration will be unaware of the intervention assignments.

The Phase 1 Perioperative Cohort will be conducted as an open-label study. Participants and investigators will be aware of the intervention assignments.