April 22, 2019
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April 23, 2019
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July 25, 2022
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July 24, 2019
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May 31, 2027 (Final data collection date for primary outcome measure)
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- Pathologic Complete Response (pCR) Rate [ Time Frame: Up to approximately 5.7 years ]
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.
- Event-Free Survival (EFS) [ Time Frame: Up to approximately 7.7 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.
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- Pathological Complete Response (pCR) Rate in All Participants [ Time Frame: Up to approximately 3 months (Time of surgery) ]
Pathological complete response rate is defined as the percentage of participants having pCR. pCR is defined as absence of viable tumor (pT0) 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) ]
Pathological 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 based on blinded independent central review (BICR) assessments, 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 based on blinded independent central review (BICR) assessments, or death due to any cause.
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- Overall Survival (OS) [ Time Frame: Up to approximately 8.4 years ]
OS is defined as the time from randomization to death due to any cause.
- Disease-Free Survival (DFS) [ Time Frame: Up to approximately 7.7 years ]
DFS is defined as the time from first post-surgery baseline scan until:
- local or distant recurrence as assessed by imaging and/or biopsy
- Death due to any cause
- Pathologic Downstaging (pDS) Rate [ Time Frame: Up to approximately 5.7 years ]
Pathologic downstaging rate is defined as the percentage of participants having pDS. pDS is defined as participants with a tumor classification of <pT2 (includes pT0, pTis, pTa, pT1) and N0 in examined tissue from RC and PLND.
- Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to approximately 8.4 years ]
An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
- Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) [ Time Frame: Up to approximately 1 year ]
An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
- Number of Participants Experiencing Perioperative Complications [ Time Frame: Up to approximately 1 year ]
The number of participants who experience perioperative complications will be presented.
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- Overall Survival (OS) in All Participants [ Time Frame: Up to approximately 6.5 years ]
OS is defined as the time from randomization to death due to any cause.
- Overall Survival in Participants Whose Tumors Express PD-L1, CPS ≥10 [ Time Frame: Up to approximately 6.5 years ]
OS is defined as the time from randomization to death due to any cause.
- Disease-Free Survival (DFS) in All Participants [ Time Frame: Up to approximately 5.5 years ]
DFS is defined as the time from first post-surgery baseline scan until:
- local or distant recurrence as assessed by imaging (BICR) and/or biopsy
- Death due to any cause
- Disease-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10 [ Time Frame: Up to approximately 5.5 years ]
DFS is defined as the time from first post-surgery baseline scan until:
- local or distant recurrence as assessed by imaging (BICR) and/or biopsy
- Death due to any cause
- Pathologic Downstaging (pDS) Rate in All Participants [ Time Frame: Up to approximately 3 months (Time of surgery) ]
Pathologic downstaging rate is defined as the percentage of participants having pDS. pDS is defined as participants with a tumor classification of <pT2 (includes pT0, pTis, pTa, pT1) and N0 in examined tissue from RC and PLND.
- Pathologic Downstaging (pDS) Rate in Participants Whose Tumors Express PD-L1, CPS ≥10 [ Time Frame: Up to approximately 3 months (Time of surgery) ]
Pathologic downstaging rate is defined as the percentage of participants having pDS. pDS is defined as participants with a tumor classification of <pT2 (includes pT0, pTis, pTa, pT1) and N0 in examined tissue from RC and PLND.
- Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to approximately 6.5 years ]
An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
- Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) [ Time Frame: Up to approximately 1 year ]
An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
- Number of Participants Experiencing Perioperative Complications [ Time Frame: Up to approximately 1 year ]
The number of participants who experience perioperative complications will be presented.
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Not Provided
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Not Provided
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Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)
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A Randomized Phase 3 Study Evaluating Cystectomy With Perioperative Pembrolizumab and Cystectomy With Perioperative Enfortumab Vedotin and Pembrolizumab Versus Cystectomy Alone in Participants Who Are Cisplatin-Ineligible or Decline Cisplatin With Muscle-Invasive Bladder Cancer (KEYNOTE-905/EV-303)
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This is a study of perioperative pembrolizumab or enfortumab vedotin in combination with pembrolizumab in participants who are cisplatin-ineligible or decline cisplatin with muscle-invasive bladder cancer (MIBC).
The primary hypothesis is that perioperative pembrolizumab plus radical cystectomy (RC) plus pelvic lymph node dissection (PLND) and perioperative enfortumab vedotin in combination with pembrolizumab plus RC+PLND will achieve superior pathologic complete response (pCR) rates (based on central pathologic review) and event-free survival (EFS) compared with RC+PLND alone.
With Amendment 5, outcome measures for programmed cell death ligand 1 (PD-L1) combined positive score (CPS) were removed.
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Not Provided
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Interventional
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Phase 3
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Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment
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Urinary Bladder Cancer, Muscle-invasive
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- Drug: Pembrolizumab
Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.
- Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
Surgical RC+PLND will be done in accordance with the American Urological Association (AUA)/American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) guidelines.
- Drug: Enfortumab Vedotin
Enfortumab vedotin 1.25 mg/kg by intravenous (IV) infusion, given on Days 1 and 8 of each 21-day cycle.
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- Experimental: Pembrolizumab + Surgery
Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by 14 cycles of postoperative pembrolizumab. Each cycle is 21 days.
Interventions:
- Drug: Pembrolizumab
- Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
- Active Comparator: Surgery alone
Participants receive standard of care surgery alone.
Intervention: Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
- Experimental: Enfortumab Vedotin + Pembrolizumab + Surgery
Participants receive 3 preoperative cycles of enfortumab vedotin + pembrolizumab, followed by standard of care surgery, followed by 6 cycles of postoperative enfortumab vedotin + pembrolizumab, followed by 8 cycles of pembrolizumab alone. Each cycle is 21 days.
Intervention: Drug: Enfortumab Vedotin
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Galsky MD, Hoimes CJ, Necchi A, Shore N, Witjes JA, Steinberg G, Bedke J, Nishiyama H, Fang X, Kataria R, Sbar E, Jia X, Siefker-Radtke A. Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303. Future Oncol. 2021 Aug;17(24):3137-3150. doi: 10.2217/fon-2021-0273. Epub 2021 May 19.
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Recruiting
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857
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610
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December 15, 2027
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May 31, 2027 (Final data collection date for primary outcome measure)
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Inclusion Criteria:
Exclusion Criteria:
- Known additional nonurothelial malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization, with certain exceptions
- Has ≥ N2 or metastatic disease (M1) as identified by imaging
- Received any prior systemic treatment, chemoradiation, and/or radiation therapy for for muscle-invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC)
- Received prior therapy with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2 (PD-L2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor
- Received prior systemic anticancer therapy including investigational agents within 3 years prior to randomization
- Received any prior radiotherapy to the bladder
- Received a partial cystectomy of the bladder to remove any non-muscle-invasive bladder cancer (NMIBC) or MIBC
- Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
- Current participation in or participation in a study of an investigational agent or use of an investigational device within 4 weeks prior to the first dose of study intervention
- Ongoing sensory or motor neuropathy Grade 2 or higher
- Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
- Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
- Severe hypersensitivity (≥ Grade 3) to enfortumab vedotin or any excipient contained in the drug formulation of enfortumab vedotin
- 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
- Active autoimmune disease that has required systemic therapy in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic therapy and is allowed
- Has uncontrolled diabetes
- History of (noninfectious) pneumonitis that required steroids, or current pneumonitis
- Active infection requiring systemic therapy
- Has had an allogenic tissue/solid organ transplant
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Sexes Eligible for Study: |
All |
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18 Years and older (Adult, Older Adult)
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No
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Australia, Belgium, Canada, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Korea, Republic of, Malaysia, Mexico, Philippines, Poland, Russian Federation, Singapore, South Africa, Spain, Sweden, Thailand, Turkey, Ukraine, United Kingdom, United States
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NCT03924895
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3475-905 MK-3475-905 ( Other Identifier: Merck ) KEYNOTE-905 ( Other Identifier: Merck ) EV-303 ( Other Identifier: Astellas Protocol Number ) PHRR210911-003890 ( Other Identifier: Philippine Health Research Registry (PHRR) ) 2018-003809-26 ( EudraCT Number )
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Yes
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Studies a U.S. FDA-regulated Drug Product: |
Yes |
Studies a U.S. FDA-regulated Device Product: |
No |
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Plan to Share IPD: |
Yes |
Plan Description: |
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf |
URL: |
http://engagezone.msd.com/ds_documentation.php |
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Merck Sharp & Dohme LLC
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Same as current
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Merck Sharp & Dohme LLC
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Same as current
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- Seagen Inc.
- Astellas Pharma Global Development, Inc.
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Study Director: |
Medical Director |
Merck Sharp & Dohme LLC |
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Merck Sharp & Dohme LLC
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July 2022
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