Bladder Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief summary
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.
Detailed description
Enrollment of participants into the Phase 1 Perioperative Cohort of this study is planned to start in approximately April of 2025.
Interventions
BIOLOGICALPembrolizumab
Administered via intravenous (IV) infusion at a dose of 400 mg on Day 1 of every 6-week cycle for up to 9 adjuvant cycles for Adjuvant Cohort participants, or at a dose of 200 mg on Day 1 of every cycle for up to four 3-week neoadjuvant cycles and up to thirteen 3-week adjuvant cycles for Perioperative Cohort participants.
BIOLOGICALIntismeran autogene
Administered via intramuscular (IM) injection at a dose of 1 mg every 3 weeks for a total of up to 9 adjuvant doses for Adjuvant Cohort participants, or at a dose of 1 mg every 3 weeks for a total of up to 9 doses in the neoadjuvant and adjuvant periods for Perioperative Cohort participants.
OTHERPlacebo
Intismeran autogene diluent only (saline and/or dextrose) administered via IM injection Q3W for up to 9 doses.
BIOLOGICALEnfortumab Vedotin
Administered via IV infusion at a dose of 1.25 mg/kg on Day 1 and Day 8 of every cycle for up to four 3-week neoadjuvant cycles and up to five 3-week adjuvant cycles for Perioperative Cohort participants.
PROCEDURESurgery (RC plus PLND)
Curative intent surgery (RC plus PLND) will be administered to all participants in the Perioperative Cohort and will be done in accordance with the American Urological Association/American Society for Radiation Oncology/American Society of Clinical Oncology/Society of Urologic Oncology guidelines. RC plus PLND will be performed within 6 weeks of the last dose of neoadjuvant intismeran autogene plus pembrolizumab plus EV treatment. Adjuvant intismeran autogene plus pembrolizumab plus EV treatment will begin within 8 weeks of completing RC plus PLND.
Sponsors
ModernaTX, Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
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.
Intervention model description
The Phase 2 Adjuvant Cohort is a placebo- and active-controlled, parallel-group, multicenter, double-blind safety and efficacy study of adjuvant intismeran autogene plus pembrolizumab versus adjuvant placebo plus pembrolizumab in participants with pathologic high-risk MIUC after radical resection. Eligible participants will be randomly assigned in a 1:1 ratio to receive treatment with either intismeran autogene plus pembrolizumab or placebo plus pembrolizumab. The Phase 1 Perioperative Cohort of this study has a single arm into which eligible participants are allocated. It will evaluate safety and preliminary efficacy of perioperative (neoadjuvant and adjuvant) intismeran autogene in combination with pembrolizumab plus EV for participants with muscle-invasive bladder cancer (MIBC).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjuvant Cohort: Disease Free Survival (DFS) | Up to approximately 28 months | DFS is defined as the time from randomization until death from any cause, or presence of disease per investigator assessment with muscle-invasive (≥pT2) disease or any high-grade non-muscle invasive disease in the urothelial tract (upper tract or lower tract) on imaging and biopsy, and/or disease recurrence outside the urothelial tract on imaging with or without confirmation by biopsy. DFS will be reported for the Adjuvant Cohort. |
| Perioperative Cohort: Number of Participants Who Experience an Adverse Event (AE) | Up to approximately 19 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who experience AEs will be reported for the Perioperative Cohort. |
| Perioperative Cohort: Number of Participants Who Discontinue Study Treatment Due to AE | Up to approximately 16 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who discontinue study treatment due to an AE will be reported for the Perioperative Cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjuvant Cohort: Number of Participants Who Discontinue Study Treatment Due to an AE | Up to approximately 13 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who discontinue study treatment due to an AE will be presented for the Adjuvant Cohort. |
| Adjuvant Cohort: Overall Survival (OS) | Up to approximately 28 months | Overall survival is defined as the time from randomization to death due to any cause. OS will be reported for the Adjuvant Cohort. |
| Perioperative Cohort: Pathologic Downstaging (pDS) Rate | Up to approximately 18 weeks | pDS is defined as participants with \<pT2 (includes pT0, pTis, pTa, pT1) and N0 in examined tissue from RC plus PLND as assessed by the investigator. pDS rate will be reported as the percentage of participants in the Perioperative Cohort having pDS. |
| Perioperative Cohort: Pathologic Complete Response (pCR) Rate | Up to approximately 18 weeks | pCR is defined as the absence of viable tumor (pT0N0) in examined tissue from RC plus PLND as assessed by the investigator. pCR rate will be reported as the percentage of participants in the Perioperative Cohort having pCR. |
| Adjuvant Cohort: Distant Metastasis-Free Survival (DMFS) | Up to approximately 28 months | DMFS is defined as the time from randomization until death from any cause, or disease recurrence outside the urothelial tract on imaging with or without confirmation by biopsy, per investigator assessment. DMFS will be reported for the Adjuvant Cohort. |
| Adjuvant Cohort: Number of Participants Who Experience an AE | Up to approximately 16 months | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who experience an AE will be reported for the Adjuvant Cohort. |
Countries
Australia, Canada, Chile, Colombia, France, Germany, Italy, New Zealand, Peru, Poland, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed