Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-Eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/ KEYNOTE-B15 / EV-304)

Merck Sharp & Dohme LLC808 enrolled

Overview

The purpose of this study is to assess the antitumor efficacy and safety of perioperative enfortumab vedotin (EV) plus pembrolizumab and radical cystectomy (RC) + pelvic lymph node dissection (PLND) compared with the current standard of care (neoadjuvant chemotherapy \[gemcitabine plus cisplatin\] and RC + PLND) for participants with MIBC who are cisplatin-eligible. The primary hypothesis is perioperative EV and pembrolizumab and RC + PLND (Arm A) will achieve superior event free survival (EFS) compared with neoadjuvant gemcitabine + cisplatin and RC + PLND (Arm B).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

808

Conditions

Bladder Cancer

Interventions

Pembrolizumab

200 mg of Pembrolizumab IV infusion, on Day 1 Q3W for 4 cycles (each cycle length = 21 days) in preoperative phase (up to approximately 3 months) and on Day 1 Q3W for 13 cycles in postoperative phase (up to approximately 9 months). The total duration of treatment is up to approximately 1 year.

Enfortumab vedotin (EV)BIOLOGICAL

1.25 mg/kg of EV IV infusion, on Day 1 and Day 8 Q3W for 4 cycles (each cycle length = 21 days) in preoperative phase (up to approximately 3 months) and on Day 1 and Day 8 Q3W for 5 cycles (each cycle length = 21 days) in postoperative phase (up to approximately 4 months). The total duration of treatment is up to approximately 7 months.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Have a histologically confirmed diagnosis of urothelial carcinoma (UC) / muscle invasive bladder cancer (MIBC) (T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology. * Have clinically non-metastatic bladder cancer (N≤1 M0) determined by imaging (computed tomography (CT) or magnetic resonance imaging (MRI) of the chest/abdomen/pelvis * Be deemed eligible for Radical Cystectomy (RC) + Pelvic Lymph Node Dissection (PLND) * Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Have adequate organ function. Exclusion Criteria: * Has a known additional malignancy that is progressing or has required active anti-cancer treatment ≤3 years of study randomization with certain exceptions * Has received any prior systemic treatment for MIBC or non-invasive muscle bladder cancer (NMIBC - prior treatment for NMIBC with intravesical BCG/chemotherapy is permitted) or prior therapy with an anti- programmed cell death 1 (PD-1), anti-programmed cell death ligand 1/ ligand 2 (PD-L1/L2), or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) * Has ≥N2 disease or metastatic disease (M1) as identified by imaging * Is cisplatin-ineligible, as defined by meeting any one of the cisplatin ineligibility criteria as per protocol * Has received prior systemic anticancer therapy including investigational agents within 3 years of randomization or any radiotherapy to the bladder * Has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC * Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention * Has a diagnosis of immunodeficiency or has a known history of human immunodeficiency virus (HIV) infection. Hepatitis B infection or known active Hepatitis C infection * Has a known psychiatric or substance abuse disorder * Has had an allogenic tissue/solid organ transplant * Has ongoing sensory or motor neuropathy Grade 2 or higher * Has active keratitis (superficial punctate keratitis) or corneal ulcerations * Has a history of uncontrolled diabetes defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to \<8% with associated diabetes symptoms

Locations (188)

Mayo Clinic in Arizona - Phoenix ( Site 0043)

Phoenix, Arizona, United States

St Joseph Heritage Healthcare-Oncology ( Site 0035)

Fullerton, California, United States

UCLA Hematology/Oncology - Westwood (Building 200 Suite 140)-Department of Urology/Institute of Uro ( Site 0005)

Los Angeles, California, United States

University of California San Francisco ( Site 0010)

San Francisco, California, United States

Stanford University ( Site 0023)

Stanford, California, United States

Outcomes

Primary Outcomes

Event-Free Survival (EFS)

EFS is defined as the time from randomization to the first occurrence of following events: radiographic disease progression precluding RC + PLND, failure to undergo surgery in participants with residual disease, gross residual disease left behind at time of surgery, local or distant recurrence based on blinded independent central review (BICR) or death due to any cause.

Time frame: Up to ~68 months

Secondary Outcomes

Pathologic Complete Response (pCR) Rate

pCR rate is defined as defined as the proportion of participants having pCR. pCR is defined as absence of viable tumor (pT0N0) in examined tissue from radical cystectomy (RC) + pelvic lymph node dissection (PLND), as assessed by blinded central pathologic review.

Time frame: Up to ~47 months

Overall Survival (OS)

OS is defined as the time from randomization to death due to any cause.

Time frame: Up to ~68 months

Disease Free Survival (DFS)

DFS is defined as the time from postsurgery baseline scan until the first occurrence of either local/distant recurrence as assessed by BICR imaging and/or biopsy or death from any cause.

Time frame: From ~12 months to up to ~68 months

Pathologic Downstaging (pDS) Rate

pDS is defined as participants with \<pT2 (includes pT0, pTis, pTa, and pT1) and N0 in examined tissue from RC plus PLND, based on central pathologic review.

Time frame: Up to ~47 months

Number of Participants Who Experienced An Adverse Event (AE) (Arm A only)

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience an AE will be presented.

Time frame: Up to ~68 months

Number of Participants Who Discontinued Study Treatment Due to An AE (Arm A only)

Time frame: Up to ~68 months

Number of Participants Experiencing Perioperative Complications

Perioperative complications are defined as both intraoperative and postoperative complications, potentially contributing to increased length of inpatient care and/or delay of adjuvant therapy. The number of participants experiencing perioperative complications will be presented.

Time frame: Up to ~68 months

Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score

The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer participants. Participant responses to questions 29 ("How would you rate your overall health during the past week?") and 30 ("How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1= Very poor to 7=Excellent). A higher score indicates a better overall health/quality of life status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined scores will be presented.