MK3475-992

1. Has a histologically confirmed diagnosis of MIBC (T2-T4aN0M0) with predominant urothelial histology (histology and presence of muscle invasion to be confirmed by BICR)

• Participants with mixed histology are eligible provided the urothelial component is ≥ 50%.

• Participants whose tumors contain any small cell or neuroendocrine component are not eligible.

• Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.

Note: A prior history of upper tract urothelial carcinoma (UTUC) treated with nephroureterectomy is eligible.

2. Has had a maximal TURBT performed within 90 days prior to randomization or during screening. Specimens that are submitted must be deemed adequate to determine PD-L1 status and evaluable for histology and muscle invasion by BICR prior to randomization.

Note: If previous TURBT performed was macroscopically incomplete, it must be repeated during screening.

Note: Specimens sent for BICR must contain a muscle invasive component (at least T2). If the specimen obtained from the most recent TURBT is deemed inadequate or non-evaluable, an archival tissue sample may be submitted. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to precut slides. If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Procedures Manual).

3. Has planned and is eligible to receive CRT and one of the protocol-specified chemotherapy regimens.

Note: The site must receive confirmation of the planned radiation field from the central vendor prior to randomization.

4. Has non-metastatic bladder cancer (N0M0) determined by imaging (CT/MRI of the chest and CTU/MRU), confirmed by BICR.

5. Has an ECOG performance status of 0, 1 or 2 assessed within 14 days prior to randomization.

6. Demonstrates adequate organ function as defined in Table 1. All screening laboratory tests should be performed within 14 days prior to randomization.

Demographics

7. Is male or female, at least 18 years of age, at the time of signing the informed consent.

Male Participants

Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study intervention

• Refrain from donating sperm

PLUS either:

• 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 (vasectomized or secondary to medical cause) as detailed below:

◦ Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.

Female Participants

Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

9. 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 WOCBP

OR

• 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), as described in [Appendix 5] during the intervention period and for at least 180 days 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 investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.

• A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention.

• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

o The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

Informed Consent

10. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research. 

Research Nurse: Amanda Cook (x4656) Amanda.Cook@lthtr.nhs.uk

Administrator: Yecora Lecanda-Swarbrick (x3766)