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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)

NCT04700124

Description:

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).

Related Conditions:
  • Bladder Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-B15
  • SECONDARY ID: MK-3475-B15
  • SECONDARY ID: KEYNOTE-B15
  • SECONDARY ID: EV-304
  • SECONDARY ID: 2020-003106-31
  • SECONDARY ID: jRCT2041210011
  • NCT ID: NCT04700124

Conditions

  • Muscle Invasive Bladder Cancer

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475Arm A: Perioperative EV+ Pembrolizumab and RC + PLND
Enfortumab vedotin (EV)PadcevArm A: Perioperative EV+ Pembrolizumab and RC + PLND
GemcitabineGemzarArm B: Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC + PLND
CisplatinPlatinol®, Platinol®-AQArm B: Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC + PLND

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Arm A: Perioperative EV+ Pembrolizumab and RC + PLNDExperimentalParticipants 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.
  • Pembrolizumab
  • Enfortumab vedotin (EV)
Arm B: Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC + PLNDExperimentalParticipants 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.
  • Gemcitabine
  • Cisplatin

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic Complete Response (pCR) Rate
Time Frame:Up to approximately 42 months
Safety Issue:
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.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to approximately 5 years
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Disease Free Survival (DFS)
Time Frame:From approximately 12 months to up to approximately 5 years
Safety Issue:
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.
Measure:Pathologic Downstaging (pDS) Rate
Time Frame:Up to approximately 42 months
Safety Issue:
Description: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.
Measure:Number of Participants Who Experienced An Adverse Event (AE) (Arm A only)
Time Frame:Up to approximately 5 years
Safety Issue:
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.
Measure:Number of Participants Who Discontinued Study Treatment Due to An AE (Arm A only)
Time Frame:Up to approximately 5 years
Safety Issue:
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.
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
Time Frame:Baseline, Up to approximately 5 years
Safety Issue:
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.
Measure:Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale
Time Frame:Baseline, Up to approximately 5 years
Safety Issue:
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.
Measure:Change From Baseline in Urinary, Bowel and Sexual Domains per Bladder Cancer Index (BCI)
Time Frame:Baseline, Up to approximately 5 years
Safety Issue:
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.
Measure: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
Safety Issue:
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.
Measure: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
Safety Issue:
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. 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.
Measure:TTD in the Physical Functioning Scale per EORTC QLQ-C30
Time Frame:Up to approximately 5 years
Safety Issue:
Description: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.
Measure:TTD in the Urinary, Bowel and Sexual Domains per BCI
Time Frame:Up to approximately 5 years
Safety Issue:
Description: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.
Measure:TTD in the EQ-5D-5L VAS
Time Frame:Up to approximately 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • 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)

Last Updated

July 16, 2021