Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)
N
Nabil Adra, MD
Primary Investigator
Administratively Closed
18 years and older
All
Phase
3
857 participants needed
2 Locations
Overview
This is a study of perioperative pembrolizumab or enfortumab vedotin in combination withbrolizumab in participants who are cisplatin-ineligible or decline cisplatin withuscle-invasive bladder cancer (MIBC).
The primary hypothesis is that perioperative pembrolizumab plus radical cystectomy (RC) plusvic lymph node dissection (PLND) and perioperative enfortumab vedotin in combination withbrolizumab plus RC+PLND will achieve superior event-free survival (EFS) compared with
RC+PLND alone.
With Amendment 5, outcome measures for programmed cell death ligand 1 (PD-L1) combinedve score (CPS) were removed.
With Amendment 8, the primary outcome measure of pathologic complete response (pCR) rates washanged to a secondary outcome measure.
Eligibility
You may be eligible for this study if you meet the following criteria:
-
Conditions:
Urinary Bladder Cancer, Muscle-invasive
-
Age: 18 Years
-
Gender: All
Inclusion Criteria:
- Have a histologically confirmed diagnosis of urothelial carcinoma/muscle-invasivebladder cancer [MIBC] (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelialhistology to be confirmed by Blinded Independent Central Review (BICR) (centralhology and/or imaging).
- Clinically nonmetastatic bladder cancer determined by imaging
- Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), andgreement to undergo curative intent standard RC + PLND (including prostatectomy ifble)
- Ineligible for treatment with cisplatin, as defined by meeting at least one of thewing criteria OR be eligible for treatment with cisplatin but decline treatmentwith cisplatin-based chemotherapy:
- Impaired renal function with measured or calculated creatinine clearance (CrCl)30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet ofRenal Disease [MDRD] equations, or measured by 24-hour urine collection)
- Eastern Cooperative Oncology Group (ECOG) Performance Status 2
- Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometrichearing loss
- New York Heart Association (NYHA) Class III heart failure
- Transurethral resection (TUR) of a bladder tumor that is submitted for central
pathology assessment and adequate to determine urothelial histology and PD-L1
- ECOG performance status of 0, 1, or 2
- Adequate organ function
- A male participant is eligible to participate if he agrees to use contraception anddonating sperm during the intervention period and for at least 180 dayshe last dose of enfortumab vedotin. If the male participants are receivingbrolizumab only or undergoing surgery only, there are no contraception requirements
- A female participant is eligible to participate if she is not pregnant, notbreastfeeding, and at least 1 of the following conditions applies: Not a (woman ofhildbearing potential) WOCBP or a WOCBP who agrees to use a highly effectiveve method or be abstinent from heterosexual intercourse (as their preferredd usual lifestyle) during the intervention period and for at least 120 days afterhe last dose of pembrolizumab and at least 180 days after the last dose of enfortumabvedotin; whichever comes last. A female participant must agree not to donate eggsduring this period as well
- A WOCBP must have a negative highly sensitive pregnancy test within 24 hours beforehe first dose of study intervention
Exclusion Criteria:
- Known additional nonurothelial malignancy that is progressing or has required active≤3 years of study randomization, with certain exceptions
- Has ≥ N2 or metastatic disease (M1) as identified by imaging
- Received any prior systemic treatment, chemoradiation, and/or radiation therapy foruscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC)
- Received prior therapy with an anti-programmed cell death protein 1 (PD-1),grammed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2(PD-L2), or with an agent directed to another stimulatory or coinhibitory T-cell
- Received prior systemic anticancer therapy including investigational agents within 3years prior to randomization
- Received any prior radiotherapy to the bladder
- Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder(NMIBC) or MIBC
- Received a live or live-attenuated vaccine within 30 days before the first dose ofudy intervention
- Current participation in or participation in a study of an investigational agent oruse of an investigational device within 4 weeks prior to the first dose of studyvention
- Ongoing sensory or motor neuropathy Grade 2 or higher
- Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or anyher form of immunosuppressive therapy within 7 days prior the first dose of studydrug. Physiologic replacement doses of corticosteroids are permitted for participantswith adrenal insufficiency.
- Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any ofheir excipients
- Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient containedhe drug formulation of enfortumab vedotin
- Active keratitis or corneal ulcerations. Participants with superficial punctatekeratitis are allowed if the disorder is being adequately treated in the opinion ofhe investigator
- Active autoimmune disease that has required systemic therapy in past 2 years (i.e.,with use of disease modifying agents, corticosteroids or immunosuppressive drugs).Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidherapy for adrenal or pituitary insufficiency) is not considered a formystemic therapy and is allowed
- Has uncontrolled diabetes
- History of (noninfectious) pneumonitis that required steroids, or current pneumonitis
- Active infection requiring systemic therapy
- Has had an allogeneic tissue/solid organ transplant
Updated on
15 May 2024.
Study ID: 3475-905, CTO-MK-3475-905, 1908546866
