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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03924895




Registration number
NCT03924895
Ethics application status
Date submitted
22/04/2019
Date registered
23/04/2019
Date last updated
17/05/2024

Titles & IDs
Public title
Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)
Scientific title
A Randomized Phase 3 Study Evaluating Cystectomy With Perioperative Pembrolizumab and Cystectomy With Perioperative Enfortumab Vedotin and Pembrolizumab Versus Cystectomy Alone in Participants Who Are Cisplatin-Ineligible or Decline Cisplatin With Muscle-Invasive Bladder Cancer (KEYNOTE-905/EV-303)
Secondary ID [1] 0 0
MK-3475-905
Secondary ID [2] 0 0
3475-905
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Urinary Bladder Cancer, Muscle-invasive 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bladder - transitional cell cancer
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pembrolizumab
Treatment: Surgery - Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
Treatment: Drugs - Enfortumab Vedotin

Experimental: Arm A: Pembrolizumab + Surgery - Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.

Active Comparator: Arm B: Surgery alone - Participants receive standard of care surgery alone.

Experimental: Arm C: Enfortumab Vedotin + Pembrolizumab + Surgery - Participants receive 3 preoperative cycles of enfortumab vedotin + pembrolizumab, followed by standard of care surgery, followed by 6 cycles of postoperative enfortumab vedotin + pembrolizumab, followed by 8 cycles of pembrolizumab alone. Each cycle is 21 days.


Treatment: Drugs: Pembrolizumab
Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.

Treatment: Surgery: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
Surgical RC+PLND will be done in accordance with the American Urological Association (AUA)/American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) guidelines.

Treatment: Drugs: Enfortumab Vedotin
Enfortumab vedotin 1.25 mg/kg by intravenous (IV) infusion, given on Days 1 and 8 of each 21-day cycle.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-Free Survival (EFS) between Arm C and Arm B
Timepoint [1] 0 0
Up to approximately 7.7 years
Secondary outcome [1] 0 0
EFS between Arm A and Arm B
Timepoint [1] 0 0
Up to approximately 7.7 years
Secondary outcome [2] 0 0
Overall Survival (OS) between Arm C and Arm B
Timepoint [2] 0 0
Up to approximately 8.4 years
Secondary outcome [3] 0 0
OS between Arm A and Arm B
Timepoint [3] 0 0
Up to approximately 8.4 years
Secondary outcome [4] 0 0
Pathologic Complete Response (pCR) Rate between Arm C and Arm B
Timepoint [4] 0 0
Up to approximately 5.7 years
Secondary outcome [5] 0 0
pCR Rate between Arm A and Arm B
Timepoint [5] 0 0
Up to approximately 5.7 years
Secondary outcome [6] 0 0
Disease-Free Survival (DFS)
Timepoint [6] 0 0
Up to approximately 7.7 years
Secondary outcome [7] 0 0
Pathologic Downstaging (pDS) Rate between Arm A and Arm B
Timepoint [7] 0 0
Up to approximately 5.7 years
Secondary outcome [8] 0 0
pDS Rate between Arm C and Arm B
Timepoint [8] 0 0
Up to approximately 5.7 years
Secondary outcome [9] 0 0
Number of Participants Experiencing Adverse Events (AEs)
Timepoint [9] 0 0
Up to approximately 8.4 years
Secondary outcome [10] 0 0
Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs)
Timepoint [10] 0 0
Up to approximately 1 year
Secondary outcome [11] 0 0
Number of Participants Experiencing Perioperative Complications
Timepoint [11] 0 0
Up to approximately 1 year

Eligibility
Key inclusion criteria
- Have a histologically confirmed diagnosis of urothelial carcinoma/muscle-invasive
bladder cancer [MIBC] (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (=50%) urothelial
histology to be confirmed by Blinded Independent Central Review (BICR) (central
pathology and/or imaging).

- Clinically nonmetastatic bladder cancer determined by imaging

- Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), and
agreement to undergo curative intent standard RC + PLND (including prostatectomy if
applicable)

- Ineligible for treatment with cisplatin, as defined by meeting at least one of the
following criteria OR be eligible for treatment with cisplatin but decline treatment
with cisplatin-based chemotherapy:

- Impaired renal function with measured or calculated creatinine clearance (CrCl)
30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet of
Renal Disease [MDRD] equations, or measured by 24-hour urine collection)

- Eastern Cooperative Oncology Group (ECOG) Performance Status 2

- Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade =2 audiometric
hearing loss

- New York Heart Association (NYHA) Class III heart failure

- Transurethral resection (TUR) of a bladder tumor that is submitted for central
pathology assessment and adequate to determine urothelial histology and PD-L1
expression assessment

- ECOG performance status of 0, 1, or 2

- Adequate organ function

- A male participant is eligible to participate if he agrees to use contraception and
refrain from donating sperm during the intervention period and for at least 180 days
after the last dose of enfortumab vedotin. If the male participants are receiving
pembrolizumab only or undergoing surgery only, there are no contraception requirements

- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least 1 of the following conditions applies: Not a (woman of
childbearing potential) WOCBP or a WOCBP who agrees to use a highly effective
contraceptive method or be abstinent from heterosexual intercourse (as their preferred
and usual lifestyle) during the intervention period and for at least 120 days after
the last dose of pembrolizumab and at least 180 days after the last dose of enfortumab
vedotin; whichever comes last. A female participant must agree not to donate eggs
during this period as well

- A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before
the first dose of study intervention
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Known additional nonurothelial malignancy that is progressing or has required active
anticancer treatment =3 years of study randomization, with certain exceptions

- Has = N2 or metastatic disease (M1) as identified by imaging

- Received any prior systemic treatment, chemoradiation, and/or radiation therapy for
for muscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer
(NMIBC)

- Received prior therapy with an anti-programmed cell death protein 1 (PD-1),
anti-programmed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2
(PD-L2), or with an agent directed to another stimulatory or coinhibitory T-cell
receptor

- Received prior systemic anticancer therapy including investigational agents within 3
years prior to randomization

- Received any prior radiotherapy to the bladder

- Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder
cancer (NMIBC) or MIBC

- Received a live or live-attenuated vaccine within 30 days before the first dose of
study intervention

- Current participation in or participation in a study of an investigational agent or
use of an investigational device within 4 weeks prior to the first dose of study
intervention

- Ongoing sensory or motor neuropathy Grade 2 or higher

- Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior the first dose of study
drug. Physiologic replacement doses of corticosteroids are permitted for participants
with adrenal insufficiency.

- Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of
their excipients

- Severe hypersensitivity (= Grade 3) to enfortumab vedotin or any excipient contained
in the drug formulation of enfortumab vedotin

- Active keratitis or corneal ulcerations. Participants with superficial punctate
keratitis are allowed if the disorder is being adequately treated in the opinion of
the investigator

- Active autoimmune disease that has required systemic therapy in past 2 years (i.e.,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic therapy and is allowed

- Has uncontrolled diabetes

- History of (noninfectious) pneumonitis that required steroids, or current pneumonitis

- Active infection requiring systemic therapy

- Has had an allogeneic tissue/solid organ transplant

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
24/07/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
15/12/2027
Actual
Sample size
Target
857
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Western Sydney Local Health District ( Site 1259) - Blacktown
Recruitment hospital [2] 0 0
Macquarie University ( Site 1251) - Macquarie Park
Recruitment hospital [3] 0 0
Cairns Base Hospital ( Site 1257) - Cairns
Recruitment hospital [4] 0 0
Mater Misericordiae Ltd ( Site 1258) - South Brisbane
Recruitment hospital [5] 0 0
Eastern Health ( Site 1255) - Box Hill
Recruitment hospital [6] 0 0
Monash Health ( Site 1260) - Clayton
Recruitment postcode(s) [1] 0 0
2148 - Blacktown
Recruitment postcode(s) [2] 0 0
2109 - Macquarie Park
Recruitment postcode(s) [3] 0 0
4870 - Cairns
Recruitment postcode(s) [4] 0 0
4101 - South Brisbane
Recruitment postcode(s) [5] 0 0
3128 - Box Hill
Recruitment postcode(s) [6] 0 0
3168 - Clayton
Recruitment outside Australia
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United States of America
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Alabama
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Arkansas
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District of Columbia
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Georgia
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Illinois
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Indiana
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Kansas
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Louisiana
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Maine
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Massachusetts
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Nara
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Osaka
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Seoul
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Taegu-Kwangyokshi
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Baskortostan, Respublika
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Russian Federation
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Ivanovskaya Oblast
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Russian Federation
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Krasnoyarskiy Kray
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Russian Federation
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Kurskaya Oblast
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Russian Federation
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Moskva
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Russian Federation
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Murmanskaya Oblast
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Russian Federation
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Nizhegorodskaya Oblast
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Russian Federation
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Omskaya Oblast
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Russian Federation
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Sankt-Peterburg
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Russian Federation
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Saratovskaya Oblast
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Russian Federation
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Sverdlovskaya Oblast
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Russian Federation
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Tyumenskaya Oblast
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Singapore
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Central Singapore
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South Africa
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Gauteng
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South Africa
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Western Cape
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Barcelona
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Gerona
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Madrid, Comunidad De
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Valenciana, Comunitat
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Spain
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Madrid
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Spain
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Sevilla
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Sweden
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Jonkopings Lan
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Sweden
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Stockholms Lan
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Sweden
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Uppsala Lan
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Sweden
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Sweden
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Vastra Gotalands Lan
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Thailand
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Krung Thep Maha Nakhon
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Thailand
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Chiang Mai
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Thailand
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Khon Kaen
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Turkey
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Ankara
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Turkey
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Istanbul
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Konya
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Sakarya
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Turkey
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Trabzon
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Ukraine
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Cherkaska Oblast
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Ukraine
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Dnipropetrovska Oblast
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Ukraine
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Kharkivska Oblast
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Khersonska Oblast
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Kyivska Oblast
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Lvivska Oblast
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Zhytomyrska Oblast
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Ukraine
State/province [173] 0 0
Kyiv
Country [174] 0 0
United Kingdom
State/province [174] 0 0
England
Country [175] 0 0
United Kingdom
State/province [175] 0 0
Hertfordshire
Country [176] 0 0
United Kingdom
State/province [176] 0 0
London, City Of
Country [177] 0 0
United Kingdom
State/province [177] 0 0
Midlothian
Country [178] 0 0
United Kingdom
State/province [178] 0 0
Truro
Country [179] 0 0
United Kingdom
State/province [179] 0 0
Walsall
Country [180] 0 0
United Kingdom
State/province [180] 0 0
Wirral

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme LLC
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Seagen Inc.
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Astellas Pharma Global Development, Inc.
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a study of perioperative pembrolizumab or enfortumab vedotin in combination with
pembrolizumab in participants who are cisplatin-ineligible or decline cisplatin with
muscle-invasive bladder cancer (MIBC).

The primary hypothesis is that perioperative pembrolizumab plus radical cystectomy (RC) plus
pelvic lymph node dissection (PLND) and perioperative enfortumab vedotin in combination with
pembrolizumab plus RC+PLND will achieve superior event-free survival (EFS) compared with
RC+PLND alone.

With Amendment 5, outcome measures for programmed cell death ligand 1 (PD-L1) combined
positive score (CPS) were removed.

With Amendment 8, the primary outcome measure of pathologic complete response (pCR) rates was
changed to a secondary outcome measure.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03924895
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03924895