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-DK
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 870
To be eligible for inclusion in this study, the participant must:
1. Have a histologically confirmed diagnosis of UC/MIBC (clinical stage T2 T4aN0M0 or T1 T4aN1M0) with predominant (=50%) urothelial histology and PD-L1 expression (CPS =10 or CPS <10, for PD-L1 CPS score not evaluable refer to inclusion criterion #4) to be confirmed by BICR (central pathology and/or imaging):
-T1 disease (eligible only with N1 disease) and T2 disease will be confirmed by central pathology review and T3, T4a, N0 and N1 disease will be confirmed by central imaging review.
-Participants with mixed histology are eligible provided the urothelial component is =50% as noted above. (Participants whose tumors contain predominant [=50%] plasmacytoid variant are not eligible.)
-Participants whose tumors contain any neuroendocrine histology are not eligible.
-UCs not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.
2. Have clinically non-metastatic bladder cancer (N=1 M0) determined by imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR.
3. Be deemed eligible for RC + PLND by a 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 TUR of a bladder tumor (obtained as early as 60days [+14days] prior to enrollment [providing documented informed consent]) that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression. (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 ECOG performance status of 0 or 1.
6. Have 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 providing documented informed consent.
8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: Pembrolizumab 0 days (no requirement), Gemcitabine and/or cisplatin: 90 days
-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.
9. Female Participant
-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), during the intervention period and for at least 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 contracept
The participant must be excluded from the study if the participant:
1. Has a known additional malignancy that is progressing or has required active anticancer treatment =3 years of study randomization
2. Has received any prior systemic treatment, chemoradiation, and/or radiation therapy for MIBC or NMIBC.
3. Has =N2 disease or metastatic disease (M1) as identified by imaging.
4. Is cisplatin-ineligible, as defined by meeting any one of the following criteria:
- Impaired renal function with measured or calculated CrCl <60 mL/min
- ECOG Performance Status =2
- CTCAE v.4 Grade =2 audiometric hearing loss (Audiometric abnormalities without corresponding clinical symptoms of Grade =2 hearing loss will not be grounds for exclusion). 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 or greater 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 prior systemic anticancer therapy including investigational agents within 3 years before randomization.
7. Has received any prior radiotherapy to the bladder.
8. Has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.
9. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
10. Is currently participating in or has participated in a study of an investigational agent or has 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 intervention. Inhaled or topical steroids are permitted in the absence of autoimmune disease. Physiologic replacement (10 mg/day prednisone equivalent) doses of corticosteroids are permitted for participants with adrenal insufficiency.
12. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its 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 (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
16. Has an active infection requiring systemic therapy (IV/oral). Participant may be rescreened once after resolution of the infection.
17. Has a known history of 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 HCV (defined as detectable HCV RNA via qualitative nucleic acid testing) infection.
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 participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating inves
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