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.   
o 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.
6. Must have an ECOG performance status of 0, 1, or 2.7. Demonstrate adequate organ function 
8. Participant is male or female at least 18 years of age, at the time of providing informed consent.
Male Participants
9. 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 enfortumab vedotin 
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies.

Criteri di esclusione: 

1. Has a known additional nonurothelial malignancy that is progressing or has required active anticancer 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 curatively-treated localized prostate cancer are not excluded; Sponsor consultation is required prior to randomization to determine eligibility in these participants. 
2. Participants with ≥N2 disease or metastatic disease (M1) as identified by imaging. 
3. Has received any prior systemic treatment, chemoradiation, and / or radiation therapy for MIBC or NMIBC. Note: Prior treatment for NMIBC with intravesical instillation therapy such as Bacillus Calmette-Guérin or intravesical chemotherapy is permitted. Prior systemic treatment (including, but not limited to, anti-PD 1/L1 treatment with pembrolizumab, etc.) received for NMIBC is not permitted.Prior/Concomitant Therapy
4. 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 coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
5. Has received prior systemic anticancer therapy including investigational agents (including enfortumab vedotin or other MMAE-based ADCs) within 3 years prior to randomization. Note:  Participants must have recovered from all AEs due to previous therapies (received >3 years prior to randomization) to ≤ Grade 1 or baseline. Participants with <Grade 2 neuropathy may be eligible.
Note: If a participant has had major surgery, recovery from any toxicity and/or complications from surgery is required prior to starting study intervention.
6. Has received any prior radiotherapy to the bladder.
7. Has received a partial cystectomy of the bladder to remove any NMIBC or MIBC.8. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.Refer to Section 6.5 for information on COVID-19 vaccines.Prior/Concurrent Clinical Study Experience
9. 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.
Note: Participants who have entered the Follow-up Phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.Diagnostic Assessments
10. Has ongoing sensory or motor neuropathy Grade 2 or higher.
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. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
12. Has hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients.
13. Has known severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20).
14. Has active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator.
15. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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.
16. Has uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
17. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
18. Has an active infection (viral, bacterial, or fungal) requiring systemic therapy. Participants may be rescreened once after resolution of the infection. Refer to Appendix 6 for country-specific requirements.
Note: Routine antimicrobial prophylaxis is permitted and participants with asymptomatic chronic infections on prophylactic treatments are allowed.
19. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. Refer to Appendix 6 for country-specific requirements.
20. 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. Refer to Appendix 6 for country-specific requirements.Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority
21. 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 investigator. 
22. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. Other Exclusions
23. Has had an allogeneic tissue/solid organ transplant. 

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: 22.11.2023

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