A Randomized Phase 3 Study Evaluating Cystectomy With Perioperative Pembrolizumab and Cystectomy With Perioperative Enfortumab Vedotin and Pembrolizumab Versus Cystectomy Alone in Cisplatin-Ineligible Participants With Muscle-Invasive Bladder Cancer - MK-3475-905 (KEYNOTE-905/EV-303)

Studio Clinico

Patologia: Carcinoma della vescica

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: III

Richiesta mandatoria di tessuto: Sì

Linee di trattamento: Adiuvante/neoadiuvante

Criteri di inclusione: 

1.Have a histologically confirmed diagnosis of MIBC cT2-T4aN0M0 or cT1-T4aN1M0 with predominant (≥50%) urothelial histology (pathologic stage pT2-T4a tumors or pT1 [only if N1] to be confirmed by BICR).
-Participants whose tumors are pT1 are eligible only with N1 disease (N1 will be confirmed by BICR)
-Participants with mixed histology are eligible provided the urothelial component is ≥50% as noted above.
-Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.
-Participants whose tumors show any one of the following variant histologies, plasmacytoid, clear cell, lipid rich, giant cell, sarcomatoid and/or neuroendocrine component are not eligible (variant histology to be confirmed locally).
2.Have clinically non-metastatic bladder cancer (N≤1M0) determined by imaging (CT or MRI of the chest/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 referenced in Appendix 8 in Section 10.8.
4.Be ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
-Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method or measured by 24-hour urine collection)
-ECOG Performance Status 2
-CTCAE v.4 Grade ≥2 audiometric hearing loss.
Note: Audiometric abnormalities without corresponding clinical symptoms of Grade ≥2 hearing loss will not be grounds for exclusion
-NYHA Class III heart failure
5.Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days [+ 14 days] prior to study enrollment [ICF signed]) that is submitted and adequate to determine pathologic stage pT2-T4a or pT1 (only if N1 confirmed by BICR), urothelial histology, 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.
Note: For confirmation of stages T2-T4a, TUR biopsy samples must include detrusor muscle, without which tumor samples will not be evaluated by central vendor.
-Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides (details pertaining to tumor tissue submission can be found in the Procedures Manual).
6.Must have an ECOG performance status of 0, 1, or 2.
7.Demonstrate adequate organ function.

Criteri di esclusione: 

1.Has a known additional non-urothelial malignancy that is progressing or has required active treatment ≤3 years of study randomization.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer) who have undergone potentially curative therapy are not excluded. Participants with prior non-muscle invasive bladder cancer (NMIBC) receiving therapy prior to randomization are not excluded. Participants with low-risk prostate cancer (T1-T2a, Gleason score ≤ 6, and PSA < 10 ng/mL) either treated with definitive intent any time prior to screening or untreated in active surveillance with PSA doubling time >1 year (based on at least 3 values determined >1 month apart) are not excluded.
2.Participants with ≥ N2 or M1 disease
3.Has received any prior systemic anti-neoplastic treatment for MIBC.
Note: Prior treatment for non-muscle invasive bladder cancer (NMIBC) with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted.

Trattamento sperimentale: 

Pembrolizumab + Surgery

Enfortumab Vedotin + Pembrolizumab + Surgery

Trattamento di controllo: 

Surgery alone

Obiettivi primari dello studio: 

- Pathologic Complete Response (pCR) Rate in All Participants [ Time Frame: Up to approximately 3 months (Time of surgery) ]
    Pathologic complete response rate is defined as the percentage of participants having pCR. pCR is defined as absence of viable tumor (pT0N0) in examined tissue from RC and PLND, as determined centrally.

- Pathologic Complete Response Rate in Participants Whose Tumors Express PD-L1 Combined Positive Score (CPS) ≥10 [ Time Frame: Up to approximately 3 months (Time of surgery) ]
    Pathologic complete response rate is defined as the percentage of participants having pCR. pCR is defined as pT0 in examined tissue from RC and PLND, as determined centrally.

- Event-Free Survival (EFS) in All Participants [ Time Frame: Up to approximately 5.5 years ]
    EFS is defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes RC surgery or failure to undergo RC surgery in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy, or death due to any cause.

- Event-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10 [ Time Frame: Up to approximately 5.5 years ]
    EFS is defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes RC surgery or failure to undergo RC surgery in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy, or death due to any cause.

Centri partecipanti

Nord Italia

Centro Italia

Sud Italia e isole

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2018-003809-26

Data di inserimento: 22.04.2021

Data di aggiornamento: 16.05.2022

Promotore

Merck Sharp & Dohme Corp.

CRO

na

Principal Investigator ITALIA

Istituto Nazionale Tumori - IRCCS Fondazione Pascale, Napoli

Riferimento: Dr.ssa Rosa Tambaro

Telefono: 0815903358

Email: r.tambaro@istitutotumori.na.it

Localita: Napoli