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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Jun 2019 → ongoing

Decision date (initial)

2024-02-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Sharp & Dohme LLC · Seagen Inc. · Astellas Pharma Inc.

External identifiers

EU CT number

2023-504932-16-00

EudraCT number

2018-003809-26

WHO UTN

U1111-1290-4057

ClinicalTrials.gov

NCT03924895

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety, Pharmacokinetic, Therapy

To compare event-free survival (EFS) between Arm C (perioperative enfortumab vedotin in combination with pembrolizumab and radical cystectomy plus pelvic lymph node dissection [RC+PLND]) and Arm B (RC+PLND).

Secondary objectives 6

1. To compare EFS between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B.
2. To compare OS between Arm C and Arm B and between Arm A and Arm B.
3. To compare pathologic complete response (pCR) rates between Arm C and Arm B and between Arm A and Arm B, based on central pathologic review.
4. To assess disease-free survival (DFS) in participants from Arm A, Arm B, and Arm C who are disease-free after surgery.
5. To compare the rates of pathologic downstaging (pDS) between Arm A and Arm B and between Arm C and Arm B.
6. To evaluate the safety and tolerability of perioperative pembrolizumab with RC+PLND and perioperative enfortumab vedotin in combination with pembrolizumab with RC+PLND.

Conditions and MedDRA coding

Muscle Invasive Bladder Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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).
2. Clinically nonmetastatic bladder cancer determined by imaging
3. Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), and agreement to undergo curative intent standard RC + PLND (including prostatectomy if applicable)
4. 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
5. ECOG performance status of 0, 1, or 2
6. Adequate organ function
7. 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
8. 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
9. A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

Exclusion criteria 19

1. Known additional nonurothelial malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization, with certain exceptions
2. Has ≥ N2 or metastatic disease (M1) as identified by imaging
3. Received any prior systemic treatment, chemoradiation, and/or radiation therapy for muscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC)
4. 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
5. Received prior systemic anticancer therapy including investigational agents within 3 years prior to randomization
6. Received any prior radiotherapy to the bladder
7. Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder cancer (NMIBC) or MIBC
8. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
9. 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
10. Ongoing sensory or motor neuropathy Grade 2 or higher
11. 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.
12. Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
13. Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained in the drug formulation of enfortumab vedotin
14. 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
15. 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
16. Has uncontrolled diabetes
17. History of (noninfectious) pneumonitis that required steroids, or current pneumonitis
18. Active infection requiring systemic therapy
19. Has had an allogeneic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event-Free Survival (EFS) between Arm C and Arm B

Secondary endpoints 11

1. EFS between Arm A and Arm B
2. Overall Survival (OS) between Arm C and Arm B
3. Overall Survival (OS) between Arm A and Arm B
4. Pathological Complete Response (pCR) Rate between Arm C and Arm B
5. pCR Rate between Arm A and Arm B
6. Disease-Free Survival (DFS)
7. Pathologic Downstaging (pDS) Rate between Arm A and Arm B
8. pDS Rate between Arm C and Arm B
9. Number of Participants Experiencing an Adverse Event (AE)
10. Number of Participants Discontinuing Study Treatment due to an AE
11. Number of Participants Experiencing Perioperative Complications

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Margot Van den Sigtenhorst-Fijlstra

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Margot Van den Sigtenhorst-Fijlstra

Third parties 3

Locations

10 EU/EEA countries · 64 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 97 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications