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 (MSD)

Status and phase: Active, not recruiting; Phase 3

Conditions: Bladder Cancer

Treatments: Biological: Enfortumab vedotin (EV); Drug: Gemcitabine; Procedure: RC + PLND; Biological: Pembrolizumab; Drug: Cisplatin

Study type: Interventional

Funder types: Industry

Identifiers

NCT04700124

jRCT2041210011 (Registry Identifier)

EV-304 (Other Identifier)

3475-B15

MK-3475-B15 (Other Identifier)

PHRR221021-005086 (Registry Identifier)

KEYNOTE-B15 (Other Identifier)

2020-003106-31 (EudraCT Number)

Details and patient eligibility

About

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).

Enrollment: 808 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

808 participants in 2 patient groups

Arm A: Perioperative EV+ Pembrolizumab and RC + PLND

Experimental group

Description:

Participants receive 4 cycles (each cycle length = 21 days) of EV intravenous (IV) infusion plus pembrolizumab IV infusion preoperatively, followed by RC + PLND, followed by 5 cycles of adjuvant EV IV infusion plus 13 cycles of adjuvant pembrolizumab IV infusion postoperatively. The total treatment duration is up to approximately 1 year.

Treatment:

Procedure: RC + PLND

Biological: Pembrolizumab

Biological: Enfortumab vedotin (EV)

Arm B: Standard of Care (SOC)-Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC + PLND

Active Comparator group

Description:

Participants receive 4 cycles (each cycle length = 21 days) of standard of care (SOC) chemotherapy (gemcitabine IV infusion plus cisplatin IV infusion) preoperatively, followed by RC + PLND. The total treatment duration is up to approximately 3 months.

Treatment:

Drug: Cisplatin

Procedure: RC + PLND

Drug: Gemcitabine