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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)

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ClinicalTrials.gov Identifier: NCT04700124
Recruitment Status : Recruiting
First Posted : January 7, 2021
Last Update Posted : September 24, 2021
Sponsor:
Collaborators:
Seagen Inc.
Astellas Pharma Inc
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
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 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).

Condition or disease Intervention/treatment Phase
Muscle Invasive Bladder Cancer Biological: Pembrolizumab Biological: Enfortumab vedotin (EV) Procedure: RC + PLND Drug: Gemcitabine Drug: Cisplatin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 784 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : April 21, 2021
Estimated Primary Completion Date : June 23, 2026
Estimated Study Completion Date : June 23, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
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.
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.
Other Names:
  • KEYTRUDA®
  • MK-3475

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.
Other Name: Padcev

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).
Other Name: Surgery

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).
Other Name: Surgery

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)
Other Name: Gemzar

Drug: Cisplatin
70 mg/m^2 of Cisplatin IV infusion, Day 1, Q3W for 4 cycles in preoperative phase (up to approximately 3 months)
Other Names:
  • Platinol®
  • Platinol®-AQ




Primary Outcome Measures :
  1. Pathologic Complete Response (pCR) Rate [ Time Frame: Up to approximately 42 months ]
    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.

  2. Event-Free Survival (EFS) [ Time Frame: Up to approximately 5 years ]
    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.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to approximately 5 years ]
    OS is defined as the time from randomization to death due to any cause.

  2. Disease Free Survival (DFS) [ Time Frame: From approximately 12 months to up to approximately 5 years ]
    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.

  3. Pathologic Downstaging (pDS) Rate [ Time Frame: Up to approximately 42 months ]
    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.

  4. Number of Participants Who Experienced An Adverse Event (AE) (Arm A only) [ Time Frame: Up to approximately 5 years ]
    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.

  5. Number of Participants Who Discontinued Study Treatment Due to An AE (Arm A only) [ Time Frame: Up to approximately 5 years ]
    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.

  6. 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 [ Time Frame: Baseline, Up to approximately 5 years ]
    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.

  7. Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale [ Time Frame: Baseline, Up to approximately 5 years ]
    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.

  8. Change From Baseline in Urinary, Bowel and Sexual Domains per Bladder Cancer Index (BCI) [ Time Frame: Baseline, Up to approximately 5 years ]
    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.

  9. Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) [ Time Frame: Baseline, Up to approximately 5 years ]
    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.

  10. Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) [ Time Frame: Up to approximately 5 years ]
    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. TTD is defined as time from baseline to first onset of EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 & 30) deterioration based on established minimal important differences (MIDs) threshold. Deterioration in the global health status/quality of life of the EORTC QLQ-C30 is defined as a 10 points or greater worsening from baseline, with or without subsequent confirmation, under a right-censoring rule.

  11. TTD in the Physical Functioning Scale per EORTC QLQ-C30 [ Time Frame: Up to approximately 5 years ]
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the 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 TTD is defined as the time from baseline to first onset of the physical functioning scale per EORTC QLQ-C30 deterioration based on established MIDs threshold. Deterioration is defined as a 10 points or greater worsening from baseline with or without subsequent confirmation, under a right-censoring rule.

  12. TTD in the Urinary, Bowel and Sexual Domains per BCI [ Time Frame: Up to approximately 5 years ]
    The 36-item 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 to better functioning and health-related quality of life. TTD is defined as time from baseline to first onset of urinary, bowel and sexual domains per BCI deterioration based on established MIDs threshold. Deterioration is defined based on the published median MIDs as a 6, 7, and 7 points or greater worsening from baseline for urinary, bowel, and sexual domains, respectively, with or without subsequent confirmation, under a right-censoring rule.

  13. TTD in the EQ-5D-5L VAS [ Time Frame: Up to approximately 5 years ]
    The EQ-5D-5L VAS records the respondent's self-rated health on a 10 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". TTD is defined as the time from baseline to first onset of EQ-5D-5L VAS deterioration based on established MIDs threshold. Deterioration in score is defined in as a 7 points or greater worsening from baseline with or without subsequent confirmation, under a right-censoring rule.



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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04700124


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
Show Show 82 study locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Seagen Inc.
Astellas Pharma Inc
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT04700124    
Other Study ID Numbers: 3475-B15
MK-3475-B15 ( Other Identifier: Merck )
KEYNOTE-B15 ( Other Identifier: Merck )
EV-304 ( Other Identifier: Merck )
2020-003106-31 ( EudraCT Number )
jRCT2041210011 ( Registry Identifier: jRCT )
First Posted: January 7, 2021    Key Record Dates
Last Update Posted: September 24, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
Programmed cell death 1 (PD-1)
Programmed Death-Ligand 1 (PD-L1)
Programmed Death-Ligand 2 (PD-L2)
Pelvic Lymph Node Dissection (PLND)
Radical Cystectomy (RC)
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Gemcitabine
Cisplatin
Pembrolizumab
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological