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A Phase 3, Randomized, Open-label Study to Evaluate Perioperative Enfortumab Vedotin Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Gemcitabine and Cisplatin in Cisplatin-eligible Participants With Muscle-invasive Bladder Cancer (KEYNOTE-B15 / EV-304)

A phase 3, randomized, open-label study to investigate the antitumor efficacy and safety of perioperative EV + 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

Study Identifier

jRCT2041210011(Registry Identifier)
PHRR221021-005086(Registry Identifier)
2020-003106-31(EudraCT Number)

Clinicaltrials.gov Identifier:

NCT04700124

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Study Details

The dual primary hypotheses are preoperative EV + pembrolizumab and RC+PLND (Arm A) will achieve superior pathologic complete response (pCR) rate and 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 Phase

Medical Condition

MIBC

Intervention Model

Parallel Assignment

Arms and Interventions

Arm	Intervention
Experimental: Arm A: Perioperative EV + Pembrolizumab and RC+PLND 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.	Drug: 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. Drug: EV 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. Procedure: RC+PLND Curative intent RC+PLND surgery will be administered to all participants randomized to Arm A and B after completion of preoperative systemic treatment (RC+PLND to be done approximately at 15 weeks from randomization).
Experimental: Arm B: Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC+PLND 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.	Procedure: RC+PLND Curative intent RC+PLND surgery will be administered to all participants randomized to Arm A and B after completion of preoperative systemic treatment (RC+PLND to be done approximately at 15 weeks from randomization). Drug: Gemcitabine 1000 mg/m² of gemcitabine IV infusion, day 1 and day 8 Q3W for 4 cycles in preoperative phase (up to approximately 3 months). Drug: Cisplatin 70 mg/m² of cisplatin IV infusion, day 1, Q3W for 4 cycles in preoperative phase (up to approximately 3 months).

Arm

Intervention

Experimental: Arm A: Perioperative EV + Pembrolizumab and RC+PLND

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.

Drug: 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.

Drug: EV

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.

Procedure: RC+PLND

Curative intent RC+PLND surgery will be administered to all participants randomized to Arm A and B after completion of preoperative systemic treatment (RC+PLND to be done approximately at 15 weeks from randomization).

Experimental: Arm B: Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC+PLND

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.

Procedure: RC+PLND

Drug: Gemcitabine

1000 mg/m² of gemcitabine IV infusion, day 1 and day 8 Q3W for 4 cycles in preoperative phase (up to approximately 3 months).

Drug: Cisplatin

70 mg/m² of cisplatin IV infusion, day 1, Q3W for 4 cycles in preoperative phase (up to approximately 3 months).

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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 (≤N1 M0) determined by imaging (CT, MRI of the chest/abdomen/pelvis)
Eligible for RC+PLND
Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Have adequate organ function

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Exclusion Criteria

Has a known additional malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization with certain exceptions
Has received any prior systemic treatment for MIBC or non–muscle-invasive 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
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 allogeneic 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

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Primary Outcomes

Event-Free Survival (EFS)

Secondary Outcomes

Overall Survival (OS)
Disease-Free Survival
Pathologic Downstaging (pDS) Rate
Number of Participants Who Experienced an Adverse Event (AE) (Arm A only)
Number of Participants Who Discontinued Study Treatment Due to an AE (Arm A only)
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
Change From Baseline in EORTC QLQ-C30 Physical Functioning Scale
Change From Baseline in Urinary, Bowel, and Sexual Domains per Bladder Cancer Index (BCI)
Change From Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS)
Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30)
TTD in the Physical Functioning Scale per EORTC QLQ-C30
TTD in the Urinary, Bowel, and Sexual Domains per BCI
TTD in the EQ-5D-5L VAS

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The safety and efficacy of these investigational compounds, or investigational uses of marketed products, have not been established. For an agent(s) whose safety and efficacy have not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

Learn how to refer your patients for the EV-304 study.

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Reference: ClinicalTrials.gov. 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) (KEYNOTE-B15) (01-07-2021). https://clinicaltrials.gov/ct2/show/nct04700124. Accessed 04-18-2022.