Urinary Bladder Neoplasms, Urothelial Cancer
Conditions
Keywords
Urologic Neoplasms, Urogenital Neoplasms, Neoplasms by Site, Neoplasms, Female Urogenital Diseases, Female Urogenital Diseases and Pregnancy, Complications, Urogenital Diseases, Urinary Bladder Diseases, Urologic Diseases, Male Urogenital Diseases, Urinary Bladder Neoplasms, Cisplatin, Fluorouracil, Mitomycin, Gemcitabine, Muscle Invasive Bladder Cancer, Enfortumab vedotin, Pembrolizumab, Urothelial Cancer, Urothelial Carcinoma, Bladder-sparing, Bladder Preservation
Brief summary
This study is being done to see how well two drugs (enfortumab vedotin and pembrolizumab) work together as a bladder preservation approach to treat patients with muscle invasive bladder cancer. The study will compare these drugs to concurrent chemoradiotherapy that is usually used to treat this cancer (standard of care). The study will enroll patients with muscle-invasive bladder cancer (MIBC) who have cancer that has not spread outside the bladder.
Detailed description
This study is being conducted to evaluate the combination of enfortumab vedotin + pembrolizumab versus standard of care concurrent chemoradiotherapy, in subjects with previously untreated muscle invasive bladder cancer. Enfortumab vedotin may be administered for up to 9 cycles or a protocol defined reason for study discontinuation occurs, whichever is first. Pembrolizumab may be administered for a maximum of 17 cycles (3-week cycles) or a protocol-defined reason for study discontinuation occurs, whichever is first. Concurrent chemoradiotherapy may be administered for a maximum of 6.5 weeks.
Interventions
DRUGEnfortumab vedotin
Enfortumab vedotin administered as an IV infusion on Days 1 and 8 of every 3-week cycle up to cycle 9.
RADIATIONConventional Radiotherapy
64 Gy in 32 fractions over 6.5 weeks administered to the participant's bladder only or the bladder and prophylactically to pelvic nodes.
RADIATIONHypofractionated Radiotherapy
55 Gy in 20 fractions over 4 weeks administered to the participant's bladder only.
DRUGCisplatin
40 mg of cisplatin per meter squared of body surface area, administered once weekly via IV infusion during radiation OR 20 mg of cisplatin per meter squared of body surface area per day on Days 1 and 2 weekly via IV infusion during radiation.
DRUGFluorouracil
500 mg per meter squared of body surface area per day on Days 1-5 (week 1) and Days 22 26 (week 3) administered as continuous IV infusion during radiation in combination with mitomycin C.
DRUGMitomycin C
12 mg per meter squared of body surface area administered as an IV bolus on Day 1 during radiation in combination with fluorouracil.
DRUGGemcitabine
100 mg per meter squared of body surface area administered once weekly via IV infusion during radiation OR 27 mg per meter squared of body surface area administered twice weekly via IV infusion during radiation
DRUGPembrolizumab
IV infusion on Day 1 of every 3-week cycle up to cycle 17.
Sponsors
Astellas Pharma Global Development, Inc.
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label
Intervention model description
A randomized, controlled, parallel-group, multicenter, open-label study of EV in combination with pembrolizumab versus an active comparator-cCRT in adult participants with MIBC who are ineligible for or have elected not to undergo cystectomy. The study is open-label, and the investigators, participants, and sponsor will be aware of the study intervention assignment. The study intervention assignment is by randomization (1:1).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology staged cT2-T4aN0M0 * Tissue comprising muscle-invasive urothelial cancer must be submitted for clinical staging at baseline * Eligible for and agree to receive chemoradiotherapy and one of the protocol-specified radiosensitizing chemotherapy regimens * Fit for systemic therapy and elect bladder preservation, including participants who are ineligible for or have elected not to undergo cystectomy * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Exclusion criteria
* Advanced or metastatic disease (N+, M1), non-urothelial carcinoma, diffuse or multifocal CIS, urothelial carcinoma or histological variant at any site outside the urinary bladder within previous 24 months prior to randomization except Ta/T1/CIS of the upper urinary tract including renal pelvis and ureter if the participant had undergone complete nephrectomy * Has received any prior systemic treatment, chemoradiation, and/or radiation for MIBC or NMIBC * Prior pelvic radiation for any reason * Inadequate bladder function * Other active malignancies within 3 years prior to randomization * Previously treated with enfortumab vedotin or other MMAE-based antibody-drug conjugates (ADCs) * Previously treated with a PD(L)-1 inhibitor, defined as a PD-1 inhibitor or PD-L1 inhibitor * Uncontrolled diabetes * Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted * Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection * Received major surgery (defined as requiring general anesthesia and \>24 hour inpatient hospitalization) within 4 weeks prior to randomization * Known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin * Known genetic disorders associated with radiosensitivity (eg, ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi syndrome) * Active keratitis or corneal ulcerations * History of autoimmune disease that has required systemic treatment in the past 2 years * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Prior allogeneic stem cell or solid organ transplant * Received a live attenuated vaccine within 30 days prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bladder-intact Event Free Survival (BI-EFS) by Blinded Independent Central Review (BICR) | Up to approximately 45.5 months | BI-EFS is defined as the time from randomization to any of the following events: histologically confirmed persistent or residual MIBC post-treatment confirmed by BICR, histologically confirmed recurrent MIBC by BICR, disease progression by BICR, cystectomy, or death from any cause. |
| Overall Survival (OS) | Up to approximately 60 months | Time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bladder-intact Event Free Survival (BI-EFS) by Investigator | Up to approximately 45.5 months | BI-EFS is defined as the time from randomization to any of the following events: histologically confirmed persistent or residual MIBC post-treatment, histologically confirmed recurrent MIBC, disease progression, cystectomy, or death from any cause. |
| Complete clinical response (cCR) rate by Blinded Independent Central Review (BICR) and Investigator | Up to approximately 60 months | cCR is defined as no radiographic evidence of residual or metastatic disease on imaging, negative cystoscopy, negative pathology except for low-grade Ta, and negative urine cytology. |
| Metastasis-Free Survival (MFS) by Blinded Independent Central Review (BICR) and Investigator | Up to approximately 60 months] | Time from randomization to radiologically or pathologically confirmed distant metastasis, or death due to any cause, whichever occurs first. |
| Time to Cystectomy | Up to approximately 60 months | The time from randomization to cystectomy. |
| Disease Free Survival (DFS) by Blinded Independent Central Review (BICR) and Investigator | Up to approximately 60 months | The time from cCR to local recurrence or distant metastases, a second primary bladder cancer, or death due to any cause, whichever occurs first. |
| Cystectomy Free Survival (CFS) | Up to approximately 60 months | The time from randomization to cystectomy or death due to any cause, whichever occurs first. |
| Number of Participants with Treatment Emergent Adverse Event (TEAE) | From start of study treatment up to 30 days after last dose of study drug (approximately up to 1.1 years) | An AE is any untoward medical occurrence in a participant who receives a study treatment without regard to possibility of causal relationship. Treatment-emergent are events between the first dose of study treatment and up to 30 days after the last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants with Serious TEAEs | From start of treatment up to 90 days after the last dose of study treatment (approximately up to 1.3 years) | An SAE is any AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/ incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 90 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
Countries
Canada, United States
Contacts
CONTACTPfizer CT.gov Call Center
STUDY_DIRECTORZejing Wang, MD/PhD
Pfizer
Outcome results
None listed