A Phase 3 Trial of Perioperative Pembrolizumab + Neoadjuvant Chemotherapy vs. Perioperative Placebo + Neoadjuvant Chemotherapy for Cis-Eligible MIBC
- Conditions
- Muscle Invasive Bladder CancerMedDRA version: 20.0Level: PTClassification code 10005003Term: Bladder cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-003808-39-GB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 790
To be eligible for inclusion in this study, the participant must:
1. Have a histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (=50%) 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% as noted above.
- Participants whose tumors contain any neuroendocrine component are not eligible.
- Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.
2. Have clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT chest and CT or MRI of the abdomen/pelvis), confirmed by BICR.
3. Be deemed eligible for RC + PLND by his/her urologist and/or oncologist and agree to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines
4. Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days prior to enrollment [ICF signed]) that is submitted and adequate to determine histology, muscle invasion, and PD-L1 status by central pathology vendor. In the event the sample is not evaluable for PD-L1, the participant will be assigned to the CPS <10 group for stratification.
5. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Have demonstrated adequate organ function (all screening labs should be performed within 14 days prior to randomization).
7. Participant is male or female and at least 18 years of age inclusive, at the time of signing the informed consent.
8. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 180 days (corresponding to time needed to eliminate any study treatment(s) [pembrolizumab and or any active combination] plus an additional 90 days [a spermatogenesis cycle] for study treatments where there is risk of clinically relevant genotoxicity) after the last dose of study treatment and refrain from donating sperm during this period.
9. A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least 1 of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP)
b. WOCBP who agrees to follow the contraceptive guidance:Contraceptive Guidance and Pregnancy Testing during the treatment period and for at least 180 days (corresponding to time needed to eliminate any study treatment(s) [pembrolizumab and or any active combination] plus 30 days [a menstruation cycle] for study treatments with risk of genotoxicity) after the last dose of study treatment.
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.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 237
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 553
1. Has a known additional malignancy that is progressing or has required active anti-cancer treatment =3years of study randomization
2. Has received any prior systemic anti-neoplastic treatment for MIBC.
3. Has an abdomino-pelvic lymph node =15 mm in the short axis.
4. Is cisplatin-ineligible, as defined by meeting any one of the following criteria:
- Impaired renal function with measured or calculated creatinine clearance (CrCl) <60 mL/min (calculated by Cockcroft-Gault method or 24-hour urine collection).
- ECOG Performance Status = 2
- CTCAE v.4 Grade =2 audiometric hearing loss (threshold shift of >25 dB averaged at 2 consecutive test frequencies in at least 1 ear; testing is not required at screening; it may be performed at investigator’s discretion)
- CTCAE v.4 Grade =2 peripheral neuropathy
- New York Heart Association (NYHA) Class III heart failure
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
6. Has received therapy with hematopoietic growth factor such as granulocyte-colony stimulating factor (G-CSF) or GM-CSF in 14 days prior to randomization.
7. Has received prior systemic anti-cancer therapy including investigational agents within 3 years of randomization.
8. Has received any prior radiotherapy to the bladder.
9. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
10. Is currently participating in or has participated in a study of an investigational agent orhas used an investigational device within 4 weeks prior to the first dose of study intervention.
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 prior the first dose of study drug.
12. Has hypersensitivity to mAbs (including pembrolizumab) and/or any of their excipients.
13. Has severe hypersensitivity (=Grade 3) to cisplatin and/or gemcitabine and any of their excipients.
14. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
16. Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection.
17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
18. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as detectable HCV RNA via qualitative nucleic acid testing) infection. Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the p
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method