Phase III study of Pembrolizumab plus chemoradiation vs chemoradiation along for patients with muscle invasive bladder cancer

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

17 Mar 2020 → ongoing

Decision date (initial)

2023-06-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2023-503500-87-00

EudraCT number

2019-004023-20

WHO UTN

U1111-1287-4190

ClinicalTrials.gov

NCT04241185

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

1. To compare bladder intact event-free survival in participants from Arm A (pembrolizumab + chemoradiotherapy) and Arm B (placebo + chemoradiotherapy), based on cystoscopy, biopsy with central pathology review (if applicable), urine cytology and radiographic assessment by blinded independent central review.

Secondary objectives 6

1. To compare overall survival between Arm A (pembrolizumab + chemoradiotherapy) and Arm B (placebo + chemoradiotherapy).
2. To evaluate rate of metastasis-free survival.
3. To evaluate time to occurrence of non–muscle-invasive bladder cancer (NMIBC).
4. To evaluate the safety and tolerability of pembrolizumab + chemoradiotherapy.
5. To evaluate changes from baseline in health-related quality of life and time to deterioration, using 2 general instruments (EORTC QLQ-C30, and EQ-5D-5L) and one disease-specific instrument BCI.
6. To evaluate time to cystectomy.

Conditions and MedDRA coding

Muscle Invasive Bladder Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Has a histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology
2. Has clinically nonmetastatic bladder cancer (N0M0)
3. Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the protocol-specified radiosensitizing chemotherapy regimens
4. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
5. Demonstrates adequate organ function
6. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of CRT treatment: Refrain from donating sperm; Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP); Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days the time needed to eliminate each study intervention after the last dose of study intervention; and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: MK-3475 - 120 days and CRT - 180 days

Exclusion criteria 19

1. Has the presence of diffuse carcinoma in situ (CIS) (multiple foci of CIS) throughout the bladder
2. Has the presence of urothelial carcinoma (UC) at any site outside of the urinary bladder in the previous 2 years except for Ta stage/T1 stage/CIS of the upper tract if the participant has undergone a complete nephroureterectomy
3. Has a known additional malignancy that is progressing or has required active therapy within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ that has undergone potentially curative therapy
4. Has the presence of bilateral hydronephrosis
5. Has limited bladder function with frequency of small amounts of urine (< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter
6. Has received prior pelvic/local radiation therapy for any reason or any antineoplastic treatment for muscle-invasive bladder cancer (MIBC). Treatment for non–muscle invasive bladder cancer (NMIBC) with intravesical instillation therapy that was completed ≥28 days prior to randomization is allowed. Prior systemic treatment of NMIBC is not permitted.
7. Received prior therapy with an anti-PD-1 (programmed cell death protein 1), anti-PD-L1 (programmed death-ligand 1), or anti-PD-L2 (programmed cell death 1 ligand 2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], OX 40, or CD137 [cluster of differentiation 137])
8. Has received a live vaccine within 30 days before the first dose of study medication
9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study medication
10. Has known severe hypersensitivity (≥Grade 3) to the selected chemotherapy regimen, and/or any of their excipients and excipients of pembrolizumab
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study medication
12. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
13. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
14. Has an active infection requiring systemic therapy
15. Has a known history of human immunodeficiency virus (HIV) infection
16. Has a known history of hepatitis B or known active hepatitis C virus infection
17. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
18. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
19. Has had an allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Bladder Intact Event-Free Survival (BI-EFS)

Secondary endpoints 14

1. Overall Survival (OS)
2. Metastasis-Free Survival (MFS)
3. Time to Occurrence of Non–Muscle-Invasive Bladder Cancer (NMIBC)
4. Number of Participants Who Experienced an Adverse Event (AE)
5. Number of Participants Who Discontinued Study Intervention Due to an AE
6. Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
7. Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
8. Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
9. Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L)
10. Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30
11. TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
12. TTD in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
13. TTD in the VAS of the EQ-5D-5L
14. Time to Cystectomy

Investigational products

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

Test 1

Placebo 1

Auxiliary 4

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

Nancy B. Davis

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Nancy B. Davis

Third parties 7

Locations

11 EU/EEA countries · 37 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 104 files

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

Application history

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