The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

Clinical Trial Details

Geo Regions

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Genitourinary Cancer

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Other or Multiple Cancer Types

Enfortumab vedotin

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)
Phase 3
NCT04700124

Active Not-enrolling

Globe
Locations

United States, Argentina, Australia, Bulgaria, Canada, China, Colombia, Croatia, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Malaysia, Philippines, Poland, Portugal, Romania, Russian Federation, Singapore, South Africa, Spain, Taiwan, Ukraine, United Kingdom

Study design

Participant Group/Arm

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.

Intervention/Treatment

BIOLOGICAL: 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.

BIOLOGICAL: Enfortumab vedotin (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).

Participant Group/Arm

ACTIVE_COMPARATOR: Arm B: Standard of Care (SOC)-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.

Intervention/Treatment

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/m\^2 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/m\^2 of Cisplatin IV infusion, Day 1, Q3W for 4 cycles in preoperative phase (up to approximately 3 months)

Key eligibility criteria

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

Key dates

Study start date
  • April 2021
Estimated primary completion date
  • December 2026

Key endpoints

Primary Outcome Measures
Outcome Measure

Event-Free Survival (EFS)

Measure Description

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 Outcome Measures:
Outcome Measure

Pathologic Complete Response (pCR) Rate

Measure Description

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

Outcome Measure

Overall Survival (OS)

Measure Description

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

Time Frame

Up to ~68 months

Outcome Measure

Disease Free Survival (DFS)

Measure Description

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

Outcome Measure

Pathologic Downstaging (pDS) Rate

Measure Description

pDS is defined as participants with \

Time Frame

Up to ~47 months

Outcome Measure

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

Measure Description

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

Outcome Measure

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

Measure Description

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 discontinue study treatment due to an AE will be presented.

Time Frame

Up to ~68 months

Outcome Measure

Number of Participants Experiencing Perioperative Complications

Measure Description

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

Outcome Measure

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

Measure Description

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.

Time Frame

Baseline, Up to ~68 months

Outcome Measure

Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale

Measure Description

The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=not at all to 4=very much). A higher score indicates a better quality of life. The change from baseline in physical function (EORTC QLQ-C30 Items 1-5) score will be presented.

Time Frame

Baseline, Up to ~68 months

Outcome Measure

Change From Baseline in Urinary, Bowel and Sexual Domains per Bladder Cancer Index (BCI)

Measure Description

The BCI is a 36-item validated, condition-specific health questionnaire to assess the quality of life among participants with bladder cancer. The BCI contains 3 domains: urinary (14 items), bowel (10 items), and sexual (12 items) with function (Likert response scale: 0 \[Never\] - 4 \[Always\]) and bother (Likert response scale: 0 \[No problem\] - 4 \[Big problem\]) subdomains. The domain and subdomain scores are standardized to a 0 to 100 point scale where higher scores correspond better functioning and health-related qualify of life. The change from baseline in the combined scores of the urinary, bowel, and sexual domains of the BCI will be presented.

Time Frame

Baseline, Up to ~68 months

Outcome Measure

Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS)

Measure Description

The EQ-5D-5L VAS records the respondent's self-rated health on a 10 centimeter (cm) vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". The change from baseline in EQ-5D-5L VAS will be presented.

Time Frame

Baseline, Up to ~68 months

Outcome Measure

Change from Baseline in EORTC QLQ-C30 Role Functioning Combined Score (Items 6-7)

Measure Description

The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "Were you limited in doing either your work or other daily activities during the past week?" and " Were you limited in pursuing your hobbies or other leisure time activities during the past week?" will be scored on a 4-point scale (1=Not at All to 4=Very Much). Higher scores indicate a better level of role functioning. Change from baseline in the role functioning (EORTC QLQ-C30 Items 6-7) combined score will be presented.

Time Frame

Baseline, Up to ~68 months

Number of participants

784

Collaborators and investigators

Sponsor: Merck Sharp & Dohme LLC

Collaborator: Seagen Inc., Astellas Pharma Inc

This information is current as of January 26th 2024.