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)
- Conditions
- Bladder Cancer
- Interventions
- Registration Number
- NCT04700124
- Lead Sponsor
- Merck Sharp & Dohme LLC
- 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 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 808
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: Perioperative EV+ Pembrolizumab and RC + PLND Enfortumab vedotin (EV) 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. Arm A: Perioperative EV+ Pembrolizumab and RC + PLND 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. Arm B: Standard of Care (SOC)-Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC + PLND 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. Arm B: Standard of Care (SOC)-Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC + PLND Cisplatin 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. Arm B: Standard of Care (SOC)-Neoadjuvant chemotherapy (gemcitabine + cisplatin) and RC + PLND Gemcitabine 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. Arm A: Perioperative EV+ Pembrolizumab and RC + PLND Pembrolizumab 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.
- Primary Outcome Measures
Name Time Method Event-Free Survival (EFS) Up to ~68 months 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
Name Time Method Disease Free Survival (DFS) From ~12 months to up to ~68 months 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.
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 Baseline, Up to ~68 months 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.
Pathologic Complete Response (pCR) Rate Up to ~47 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.
Pathologic Downstaging (pDS) Rate Up to ~47 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.
Number of Participants Who Experienced An Adverse Event (AE) (Arm A only) Up to ~68 months 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.
Change From Baseline in Urinary, Bowel and Sexual Domains per Bladder Cancer Index (BCI) Baseline, Up to ~68 months 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.
Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) Baseline, Up to ~68 months 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.
Change from Baseline in EORTC QLQ-C30 Role Functioning Combined Score (Items 6-7) Baseline, Up to ~68 months 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.
Overall Survival (OS) Up to ~68 months OS is defined as the time from randomization to death due to any cause.
Number of Participants Who Discontinued Study Treatment Due to An AE (Arm A only) Up to ~68 months 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.
Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale Baseline, Up to ~68 months 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.
Number of Participants Experiencing Perioperative Complications Up to ~68 months 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.
Trial Locations
- Locations (188)
Mayo Clinic in Arizona - Phoenix ( Site 0043)
🇺🇸Phoenix, Arizona, United States
St Joseph Heritage Healthcare-Oncology ( Site 0035)
🇺🇸Fullerton, California, United States
UCLA Hematology/Oncology - Westwood (Building 200 Suite 140)-Department of Urology/Institute of Uro ( Site 0005)
🇺🇸Los Angeles, California, United States
University of California San Francisco ( Site 0010)
🇺🇸San Francisco, California, United States
Stanford University ( Site 0023)
🇺🇸Stanford, California, United States
University of Colorado, Anschutz Cancer Pavilion ( Site 0009)
🇺🇸Aurora, Colorado, United States
UF Health ( Site 0031)
🇺🇸Gainesville, Florida, United States
Indiana University Melvin and Bren Simon Cancer Center ( Site 0050)
🇺🇸Indianapolis, Indiana, United States
University of Iowa Hospital and Clinics ( Site 0029)
🇺🇸Iowa City, Iowa, United States
University of Louisville, James Graham Brown Cancer Center ( Site 0022)
🇺🇸Louisville, Kentucky, United States
Scroll for more (178 remaining)Mayo Clinic in Arizona - Phoenix ( Site 0043)🇺🇸Phoenix, Arizona, United States