Metastatic Urothelial CarcinomaPhase 1/2NCT05845814
A Study of Efficacy and Safety of Pembrolizumab Plus Enfortumab Vedotin (EV) +/- Investigational Agents in First-Line Metastatic Urothelial Carcinoma (mUC) (MK-3475-04B/KEYMAKER-U04)
A Phase 1/2 study testing Coformulated favezelimab/pembrolizumab, Coformulated vibostolimab/pembrolizumab and EV in people with Metastatic Urothelial Carcinoma and Urothelial Neoplasms, run by Merck Sharp & Dohme LLC at 47 sites in 12 countries.
Trial summary
This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the efficacy and safety of coformulated favezelimab/pembrolizumab plus EV and coformulated vibostolimab/pembrolizumab plus EV relative to pembrolizumab plus… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Urothelial Carcinoma, Urothelial Neoplasms
- What is being tested?
- Coformulated favezelimab/pembrolizumab, Coformulated vibostolimab/pembrolizumab and EV
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 390 participants
- Where
- 47 sitesin 12 countries
- Study dates
- 23 Jun 2023to 31 May 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).
- Participants with mixed histology are eligible provided the urothelial component is ≥50% (and <10% plasmacytoid component)
- Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally)
- Must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) are permitted:
- Participants that received neoadjuvant or adjuvant chemotherapy are permitted.
- Participants who received anti- programmed cell death 1 protein (PD-1) or programmed cell death ligand 1 (PD-L1) therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence >12 months from completion of therapy are permitted.
- Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
- Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement or with <Grade 2 neuropathy are eligible.
Who cannot join
- Has a known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
- Central nervous system (CNS) metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.
- Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
- Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
- Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
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- Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.
- Has a history of uncontrolled diabetes.
- Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
- Has an active infection (viral, bacterial, or fungal) requiring systemic therapy.
- Has a known history of human immunodeficiency virus (HIV) infection.
- Has hepatitis B or hepatitis C virus infection.
- Has had major surgery within 4 weeks prior to first dose of study intervention.
- Has had an allogenic tissue/solid organ transplant
Trial locations and contacts
47 sites in 12 countries.
47 sites in 12 countries
United States14 sites
Emory University School of Medicine ( Site 3043)
Atlanta, Georgia, 30322
Anschutz Cancer Pavilion ( Site 3017)
Aurora, Colorado, 80045
Dana-Farber Cancer Institute ( Site 3047)
Boston, Massachusetts, 02115
Cleveland Clinic-Taussig Cancer Center ( Site 3036)
Cleveland, Ohio, 44195
Duke Cancer Institute ( Site 3027)
Durham, North Carolina, 27710
Indiana University Melvin and Bren Simon Cancer Center ( Site 3011)
Indianapolis, Indiana, 46202
Moores Cancer Center ( Site 3028)
La Jolla, California, 92093-0698
Icahn School of Medicine at Mount Sinai ( Site 3018)
New York, New York, 10029
Memorial Sloan Kettering Cancer Center ( Site 3031)
New York, New York, 10065
University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 3045)
Orange, California, 92868
UPMC Hillman Cancer Center ( Site 3014)
Pittsburgh, Pennsylvania, 15232
Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 3041)
Salt Lake City, Utah, 84112
UCSF Medical Center at Mission Bay ( Site 3044)
San Francisco, California, 94158
Siteman Cancer Center ( Site 3038)
St Louis, Missouri, 63108
France5 sites
CHU de Bordeaux Hop St ANDRE ( Site 3607)
Bordeaux, Aquitaine, 33075
Centre Georges François Leclerc-Centre de recherche clinique ( Site 3608)
Dijon, Cote-d Or, 21079
Hôpital Européen Georges Pompidou ( Site 3605)
Paris, 75015
centre hospitalier lyon sud ( Site 3606)
Pierre-Bénite, Rhone, 69310
Oncopole Claudius Regaud ( Site 3610)
Toulouse, Haute-Garonne, 31059
Chile4 sites
Bradford Hill Norte ( Site 3152)
Antofagasta, 1240000
FALP-UIDO ( Site 3151)
Santiago, Region M. de Santiago, 7500921
Bradfordhill-Clinical Area ( Site 3155)
Santiago, Region M. de Santiago, 8420383
ONCOCENTRO APYS-ACEREY ( Site 3158)
Viña del Mar, Valparaiso, 2520598
Canada3 sites
The Ottawa Hospital - General Campus-The Ottawa Hospital Cancer Centre ( Site 3105)
Ottawa, Ontario, K1H 8L6
Sunnybrook Research Institute - Odette Cancer Centre ( Site 3108)
Toronto, Ontario, M4N 3M5
Princess Margaret Cancer Centre ( Site 3106)
Toronto, Ontario, M5G 2M9
Israel3 sites
Rambam Health Care Campus-Oncology Division ( Site 3501)
Haifa, 3109601
Rabin Medical Center-Oncology ( Site 3504)
Petah Tikva, 4941492
Sheba Medical Center-ONCOLOGY ( Site 3503)
Ramat Gan, 5265601
Italy3 sites
Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 3405)
Milan, Lombardy, 20133
Ospedale San Raffaele-Oncologia Medica ( Site 3403)
Milan, 20132
Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 3406)
Naples, Campania, 80131
Netherlands3 sites
Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 3302)
Amsterdam, North Holland, 1066 CX
Maastricht UMC+ ( Site 3304)
Maastricht, Limburg, 6229 HX
Erasmus Medisch Centrum-Medical Oncology ( Site 3303)
Rotterdam, South Holland, 3015 GD
South Korea3 sites
Severance Hospital, Yonsei University Health System-Medical oncology ( Site 3903)
Seoul, 03722
Asan Medical Center-Department of Oncology ( Site 3901)
Seoul, 05505
Samsung Medical Center ( Site 3902)
Seoul, 06351
Taiwan3 sites
Chang Gung Memorial Hospital at Kaohsiung-Oncology and Hematology ( Site 3802)
Kaohsiung City, 83301
National Cheng Kung University Hospital-Clinical Trial Center ( Site 3803)
Tainan, 704
National Taiwan University Hospital-Oncology ( Site 3801)
Taipei, 10002
Australia2 sites
Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Site 3951)
Brisbane, Queensland, 4029
Austin Health-Cancer Clinical Trials Centre ( Site 3950)
Heidelberg, Victoria, 3084
Spain2 sites
Hospital Universitari Vall d'Hebron ( Site 3767)
Barcelona, Catalonia, 08035
Hospital Clinico San Carlos ( Site 3765)
Madrid, 28040
United Kingdom2 sites
St Bartholomew's Hospital-Centre for Experimental Cancer Medicine ( Site 3206)
London, London, City of, EC1A 7BE
ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 3201)
London, London, City of, SW3 6JJ
About this study
Official title: A Phase 1/2 Randomized, Umbrella Study to Evaluate the Safety and Efficacy of Pembrolizumab Plus Enfortumab Vedotin (EV) in Combination With Investigational Agents Versus Pembrolizumab Plus EV, as First-Line Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04B
This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the efficacy and safety of coformulated favezelimab/pembrolizumab plus EV and coformulated vibostolimab/pembrolizumab plus EV relative to pembrolizumab plus EV. There will be no comparison of coformulated favezelimab/pembrolizumab plus EV versus coformulated vibostolimab/pembrolizumab plus EV. If ORR and/or DRR are substantially better on coformulated favezelimab/pembrolizumab plus EV and/or coformulated vibostolimab/pembrolizumab plus EV compared with pembrolizumab plus EV, after evaluation of the totality of data, the sponsor might consider Part 2 (expansion) to further characterize the efficacy and safety of the treatment arms under study.
Read the detailed description
The master study for this substudy is MK-3475-U04/KEYMAKER-U04. The master study will not be screening any participants and will not be registered.
With Amendment 2, participants will discontinue treatment with coformulated vibostolimab/pembrolizumab (Arm B) and be transitioned to pembrolizumab only. Per protocol, no analysis of Part 2 primary or secondary outcome measures (including efficacy or safety) will occur since Part 2 of the study will no longer take place.
- Being tested
- Coformulated favezelimab/pembrolizumab, Coformulated vibostolimab/pembrolizumab, EV, Pembrolizumab
- Medical subject headings
- Carcinoma, Transitional Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Coformulated favezelimab/pembrolizumabBiological
Also called MK-4280A
Coformulated favezelimab/pembrolizumab (800 mg/200 mg) IV infusion
Coformulated vibostolimab/pembrolizumabBiological
Also called MK-7684A
Coformulated vibostolimab/pembrolizumab (200 mg/200 mg) IV infusion
EVCombination product
Also called Padcev, ASG-22CE, ASG-22ME
1.25 mg/kg IV infusion
PembrolizumabBiological
Also called MK-3475, KEYTRUDA®
200 mg IV infusion
| Study group | Role | What they receive |
|---|---|---|
| Arm A: Coformulated favezelimab/pembrolizumab plus EV | Experimental | Participants will receive coformulated favezelimab/pembrolizumab (800 mg/200 mg) as an intravenous (IV) infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. Receives: Biological: Coformulated favezelimab/pembrolizumab; Combination Product: EV |
| Arm B: Coformulated vibostolimab/pembrolizumab plus EV | Experimental | Participants will receive coformulated vibostolimab/pembrolizumab (200 mg/200 mg) as an IV infusion on Day 1 of every 3-week cycle, for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. Receives: Biological: Coformulated vibostolimab/pembrolizumab; Combination Product: EV |
| Arm C: Pembrolizumab plus EV | Active comparator | Participants will receive 200 mg pembrolizumab as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle, until disease progression, intolerable toxicity, or investigator decision. Receives: Combination Product: EV; Biological: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part 1: Objective Response Rate (ORR)
ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). ORR will be reported for participants in Part 1.
Measured: Up to ~4 years
Part 1: Percentage of Participants experiencing an Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 1 will be reported.
Measured: Up to ~4 years
Part 1: Percentage of Participants who Discontinue study interventions due to an AE
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study interventions due to an AE in Part 1 will be reported.
Measured: Up to ~4 years
Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). The number of participants who experience a DLT in Part 1 will be reported.
Measured: Up to 21 days
Part 2: Progression Free Survival (PFS)
PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. PFS will be reported for participants in Part 2.
Measured: Up to ~4 years
Secondary outcomes (20)
Part 1: PFS
PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. PFS will be reported for participants in Part 1.
Measured: Up to ~4 years
Part 1: Duration of Response (DOR)
For participants who demonstrate confirmed CR or PR, DOR is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. DOR will be reported for participants in Part 1.
Measured: Up to ~4 years
Part 2: Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. OS will be reported for participants in Part 2.
Measured: Up to ~4 years
Part 2: ORR
ORR is defined as the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as assessed by BICR. ORR will be reported for participants in Part 2.
Measured: Up to ~4 years
Part 2: DOR
For participants who demonstrate confirmed CR or PR, DOR is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. DOR will be reported for participants in Part 2.
Measured: Up to ~4 years
Part 2: Percentage of Participants experiencing an Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 2 will be reported.
Measured: Up to ~4 years
Part 2: Percentage of Participants who Discontinue study interventions due to an AE
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study interventions due to an AE in Part 2 will be reported.
Measured: Up to ~4 years
Part 2: Percentage of Participants with Dose-limiting toxicities (DLT)
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). The number of participants who experience a DLT in Part 2 will be reported.
Measured: Up to 21 days
Part 1: Mean Change from baseline in the global health status/quality of life of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLC-C30) (Items 29 and 30)
Participants are asked to answer questions 29 and 30 from the EORTC QLC-C30. Questions 29 and 30 use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. The mean change from baseline will be reported for Part 1.
Measured: Baseline and up to ~4 years
Part 1: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30
Participants are asked to answer questions about their physical functioning from the EORTC QLC-C30. These questions use a 4-point scale (1=not at all to 4=very much) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. The mean change from baseline will be reported for Part 1.
Measured: Baseline and up to ~4 years
Part 1: Mean Change from Baseline in the European Quality of Life 5 Dimensions, 5-level Questionnaire (EQ-5D-5L) visual analog score (VAS)
The EQ-5D-5L is a descriptive five-dimensional system of evaluation. The five dimensions are mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Participants rate each dimension on 5 levels ranging from 1 (no problems) to 5 (extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates their general state of health. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. The mean change from baseline will be reported for Part 1.
Measured: Baseline and up to ~4 years
Part 2: Mean Change from baseline in the global health status/quality of life of the EORTC QLC-C30 (Items 29 and 30)
Participants are asked to answer questions 29 and 30 from the EORTC QLC-C30. Questions 29 and 30 use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. The mean change from baseline will be reported for Part 2.
Measured: Baseline and up to ~4 years
Part 2: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30
Participants are asked to answer questions about their physical functioning from the EORTC QLC-C30. These questions use a 4-point scale (1=not at all to 4=very much) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. The mean change from baseline will be reported for Part 2.
Measured: Baseline and up to ~4 years
Part 2: Mean Change from Baseline in the EQ-5D-5L visual analog score (VAS)
The EQ-5D-5L is a descriptive five-dimensional system of evaluation. The five dimensions are mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Participants rate each dimension on 5 levels ranging from 1 (no problems) to 5 (extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates their general state of health. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. The mean change from baseline will be reported for Part 2.
Measured: Baseline and up to ~4 years
Part 1: Time-to-Deterioration (TTD) for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)
Participants are asked to answer questions 29 and 30 from the EORTC QLC-C30. Questions 29 and 30 use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. TTD is defined as the time from the first GHS/QoL assessment to deterioration (defined as ≥10-point decrease in GHS/QoL score from baseline) or death, whichever occurs first. The TTD in GHS/QoL score of participants will be reported for Part 1.
Measured: Up to ~4 years
Part 1: TTD for the physical functioning scale of the EORTC QLQ-C30
Participants are asked to answer questions about their physical functioning from the EORTC QLC-C30. These questions use a 4-point scale (1=not at all to 4=very much) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. TTD is defined as the time from the first GHS/QoL assessment to deterioration (defined as ≥10-point decrease in GHS/QoL score from baseline) or death, whichever occurs first. The TTD in GHS/QoL score of participants will be reported for Part 1.
Measured: Up to ~4 years
Part 1: TTD for the EQ-5D-5L VAS
The EQ-5D-5L is a descriptive five-dimensional system of evaluation. The five dimensions are mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Participants rate each dimension on 5 levels ranging from 1 (no problems) to 5 (extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates their general state of health. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. TTD is defined as the time from the first EQ-5D-5L VAS assessment to deterioration (defined as ≥7-point decrease in EQ-5D-5L VAS score more from baseline) or death, whichever occurs first. The TTD in EQ-5D-5L VAS score of participants will be reported for Part 1.
Measured: Up to ~4 years
Part 2: TTD for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)
Participants are asked to answer questions 29 and 30 from the EORTC QLC-C30. Questions 29 and 30 use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. TTD is defined as the time from the first GHS/QoL assessment to deterioration (defined as ≥10-point decrease in GHS/QoL score from baseline) or death, whichever occurs first. The TTD in GHS/QoL score of participants will be reported for Part 2.
Measured: Up to ~4 years
Part 2: TTD for the physical functioning scale of the EORTC QLQ-C30
Participants are asked to answer questions about their physical functioning from the EORTC QLC-C30. These questions use a 4-point scale (1=not at all to 4=very much) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. TTD is defined as the time from the first GHS/QoL assessment to deterioration (defined as ≥10-point decrease in GHS/QoL score from baseline) or death, whichever occurs first. The TTD in GHS/QoL score of participants will be reported for Part 2.
Measured: Up to ~4 years
Part 2: TTD for the EQ-5D-5L VAS
The EQ-5D-5L is a descriptive five-dimensional system of evaluation. The five dimensions are mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Participants rate each dimension on 5 levels ranging from 1 (no problems) to 5 (extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates their general state of health. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. TTD is defined as the time from the first EQ-5D-5L VAS assessment to deterioration (defined as ≥7-point decrease in EQ-5D-5L VAS score more from baseline) or death, whichever occurs first. The TTD in EQ-5D-5L VAS score of participants will be reported for Part 2.
Measured: Up to ~4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2023
- Study start23 Jun 2023
- Primary completion31 May 2027 (estimated)
- Study completion31 May 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Urothelial CarcinomaStudies of the same condition, open and under way.
- More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- In Part 1, participants will be randomized in a 1:1:1 ratio to receive either Arm A (coformulated favezelimab/pembrolizumab plus EV), Arm B (coformulated vibostolimab/pembrolizumab plus EV), or Arm C (pembrolizumab plus EV). If Part 2 is conducted, participants will be randomized in a 1:1:1 ratio to Arms A, B, and C or in a 1:1 ratio to Arms A and C or B and C, depending on the treatment arm(s) that are expanded in Part 2.
- Masking
- None (open label)
- Enrolment
- 390 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Merck Sharp & Dohme LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Merck Sharp & Dohme LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05845814
- Sponsor's protocol ID
- 3475-04B
- Other IDs
- MK-3475-04B, 2023-506385-30-00, U1111-1293-7564, 2022-001371-14, 2023
- Status last verified
- Sep 2025
- First submitted
- 26 Apr 2023
- Last updated
- 10 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf
Study at a glance
From the registry record, last updated by the sponsor on 10 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/2 Randomized, Umbrella Study to Evaluate the Safety and Efficacy of Pembrolizumab Plus Enfortumab Vedotin (EV) in Combination With Investigational Agents Versus Pembrolizumab Plus EV, as First-Line Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04B
- ClinicalTrials.gov ID
- NCT05845814
- Acronym / sponsor ID
- 3475-04B
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 390 participants (estimated)
- Lead sponsor
- Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
- Study start
- 23 Jun 2023 (actual)
- Primary completion
- 31 May 2027 (estimated)
- Study completion
- 31 May 2027 (estimated)
- First posted
- 6 May 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the efficacy and safety of coformulated favezelimab/pembrolizumab plus EV and coformulated vibostolimab/pembrolizumab plus EV relative to pembrolizumab plus EV. There will be no comparison of coformulated favezelimab/pembrolizumab plus EV versus coformulated vibostolimab/pembrolizumab plus EV. If ORR and/or DRR are substantially better on coformulated favezelimab/pembrolizumab plus EV and/or coformulated vibostolimab/pembrolizumab plus EV compared with pembrolizumab plus EV, after evaluation of the totality of data, the sponsor might consider Part 2 (expansion) to further characterize the efficacy and safety of the treatment arms under study.
Detailed description
The master study for this substudy is MK-3475-U04/KEYMAKER-U04. The master study will not be screening any participants and will not be registered.
With Amendment 2, participants will discontinue treatment with coformulated vibostolimab/pembrolizumab (Arm B) and be transitioned to pembrolizumab only. Per protocol, no analysis of Part 2 primary or secondary outcome measures (including efficacy or safety) will occur since Part 2 of the study will no longer take place.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- In Part 1, participants will be randomized in a 1:1:1 ratio to receive either Arm A (coformulated favezelimab/pembrolizumab plus EV), Arm B (coformulated vibostolimab/pembrolizumab plus EV), or Arm C (pembrolizumab plus EV). If Part 2 is conducted, participants will be randomized in a 1:1:1 ratio to Arms A, B, and C or in a 1:1 ratio to Arms A and C or B and C, depending on the treatment arm(s) that are expanded in Part 2.
| Arm | Type | Receives |
|---|---|---|
| Arm A: Coformulated favezelimab/pembrolizumab plus EV | Experimental | Biological: Coformulated favezelimab/pembrolizumab, Combination Product: EVParticipants will receive coformulated favezelimab/pembrolizumab (800 mg/200 mg) as an intravenous (IV) infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. |
| Arm B: Coformulated vibostolimab/pembrolizumab plus EV | Experimental | Biological: Coformulated vibostolimab/pembrolizumab, Combination Product: EVParticipants will receive coformulated vibostolimab/pembrolizumab (200 mg/200 mg) as an IV infusion on Day 1 of every 3-week cycle, for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. |
| Arm C: Pembrolizumab plus EV | Active comparator | Combination Product: EV, Biological: PembrolizumabParticipants will receive 200 mg pembrolizumab as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle, until disease progression, intolerable toxicity, or investigator decision. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).
- Must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) are permitted:
- Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
- Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement or with <Grade 2 neuropathy are eligible.
Key exclusion criteria (14 listed)
- Has a known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
- Central nervous system (CNS) metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.
- Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
- Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Coformulated favezelimab/pembrolizumabAlso: MK-4280ACoformulated favezelimab/pembrolizumab (800 mg/200 mg) IV infusion | Biological | Arm A: Coformulated favezelimab/pembrolizumab plus EV |
| Coformulated vibostolimab/pembrolizumabAlso: MK-7684ACoformulated vibostolimab/pembrolizumab (200 mg/200 mg) IV infusion | Biological | Arm B: Coformulated vibostolimab/pembrolizumab plus EV |
| EVAlso: Padcev, ASG-22CE, ASG-22ME1.25 mg/kg IV infusion | Combination product | Arm A: Coformulated favezelimab/pembrolizumab plus EV, Arm B: Coformulated vibostolimab/pembrolizumab plus EV, Arm C: Pembrolizumab plus EV |
| PembrolizumabAlso: MK-3475, KEYTRUDA®200 mg IV infusion | Biological | Arm C: Pembrolizumab plus EV |
Primary outcome
Part 1: Objective Response Rate (ORR)
Time frame: Up to ~4 years
ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). ORR will be reported for participants in Part 1.
Part 1: Percentage of Participants experiencing an Adverse Event (AE)
Time frame: Up to ~4 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 1 will be reported.
Part 1: Percentage of Participants who Discontinue study interventions due to an AE
Time frame: Up to ~4 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study interventions due to an AE in Part 1 will be reported.
Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)
Time frame: Up to 21 days
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). The number of participants who experience a DLT in Part 1 will be reported.
Part 2: Progression Free Survival (PFS)
Time frame: Up to ~4 years
PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. PFS will be reported for participants in Part 2.
20 secondary outcomes
Part 1: PFS
Time frame: Up to ~4 years
Part 1: Duration of Response (DOR)
Time frame: Up to ~4 years
Part 2: Overall Survival (OS)
Time frame: Up to ~4 years
Part 2: ORR
Time frame: Up to ~4 years
Part 2: DOR
Time frame: Up to ~4 years
Part 2: Percentage of Participants experiencing an Adverse Event (AE)
Time frame: Up to ~4 years
Part 2: Percentage of Participants who Discontinue study interventions due to an AE
Time frame: Up to ~4 years
Part 2: Percentage of Participants with Dose-limiting toxicities (DLT)
Time frame: Up to 21 days
Part 1: Mean Change from baseline in the global health status/quality of life of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLC-C30) (Items 29 and 30)
Time frame: Baseline and up to ~4 years
Part 1: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30
Time frame: Baseline and up to ~4 years
Part 1: Mean Change from Baseline in the European Quality of Life 5 Dimensions, 5-level Questionnaire (EQ-5D-5L) visual analog score (VAS)
Time frame: Baseline and up to ~4 years
Part 2: Mean Change from baseline in the global health status/quality of life of the EORTC QLC-C30 (Items 29 and 30)
Time frame: Baseline and up to ~4 years
Part 2: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30
Time frame: Baseline and up to ~4 years
Part 2: Mean Change from Baseline in the EQ-5D-5L visual analog score (VAS)
Time frame: Baseline and up to ~4 years
Part 1: Time-to-Deterioration (TTD) for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)
Time frame: Up to ~4 years
Part 1: TTD for the physical functioning scale of the EORTC QLQ-C30
Time frame: Up to ~4 years
Part 1: TTD for the EQ-5D-5L VAS
Time frame: Up to ~4 years
Part 2: TTD for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)
Time frame: Up to ~4 years
Part 2: TTD for the physical functioning scale of the EORTC QLQ-C30
Time frame: Up to ~4 years
Part 2: TTD for the EQ-5D-5L VAS
Time frame: Up to ~4 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Sep 2025.
- Merck Clinical Trials InformationLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Merck Sharp & Dohme LLC
47 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Coformulated favezelimab/pembrolizumab, Coformulated vibostolimab/pembrolizumab and EV in people with Metastatic Urothelial Carcinoma and Urothelial Neoplasms, run by Merck Sharp & Dohme LLC at 47 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 10 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 47 sites in United States, France, Chile, Canada, Israel and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part 1: Objective Response Rate (ORR) (time frame: Up to ~4 years). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2025.