Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)

• ClinicalTrials.gov Identifier: NCT03924895
• Recruitment Status: Recruiting
• First Posted: April 23, 2019
• Last Update Posted: July 23, 2021
• Sponsor: Merck Sharp & Dohme Corp.
• Collaborators: Seagen Inc.; Astellas Pharma Global Development, Inc.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Tracking Information

• First Submitted Date: April 22, 2019
• First Posted Date: April 23, 2019
• Last Update Posted Date: July 23, 2021
• Actual Study Start Date: July 24, 2019
• Estimated Primary Completion Date: June 26, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 7, 2020)

• 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.

Original Primary Outcome Measures (submitted: April 22, 2019)

• 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.

Current Secondary Outcome Measures (submitted: July 7, 2020)

• 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 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 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.

Original Secondary Outcome Measures (submitted: April 22, 2019)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)
• Official Title: 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 (KEYNOTE-905/EV-303)
• Brief Summary: A global, randomized phase III study to evaluate perioperative pembrolizumab with radical cystectomy + pelvic lymph node dissection (RC+PLND) versus RC+PLND alone in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urinary Bladder Cancer, Muscle-invasive

Intervention

• Drug: Pembrolizumab
  Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.
  Other Names:

  • KEYTRUDA®
  • MK-3475
• 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.
  Other Names:

  • Padcev
  • ASG-22CE
  • ASG-22ME

Study Arms

• 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

• Publications *: 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 May 19. doi: 10.2217/fon-2021-0273. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 7, 2020): 836
• Original Estimated Enrollment (submitted: April 22, 2019): 610
• Estimated Study Completion Date: May 12, 2027
• Estimated Primary Completion Date: June 26, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Have a histologically confirmed diagnosis of urothelial carcinoma (cT2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology and programmed cell death ligand 1 (PD-L1) expression assessment to be confirmed by Blinded Independent Central Review (BICR) (central pathology and/or imaging).
• Clinically non-metastatic bladder cancer determined by imaging
• Eligible for radical cystectomy (RC) + pelvic lymph node dissection (PLND), and agreement to undergo curative intent standard RC + PLND (including prostatectomy if applicable)

• Ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:

  • Impaired renal function with measured or calculated creatinine clearance (CrCl) 30 to 59 mL/min (calculated by Cockcroft-Gault method, Modification of Diet of Renal Disease [MDRD] equations, or measured by 24-hour urine collection)
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 2
  • Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric hearing loss
  • New York Heart Association (NYHA) Class III heart failure
• Transurethral resection (TUR) of a bladder tumor that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression assessment.
• ECOG performance status of 0, 1, or 2
• Adequate organ function
• A male participant is eligible to participate if he agrees to use contraception and refrain from donating sperm during the intervention period and for at least 180 days after the last dose of enfortumab vedotin. If the male participants are receiving pembrolizumab only or undergoing surgery only, there are no contraception requirements.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a (woman of childbearing potential) WOCBP or a WOCBP who agrees to use a highly effective contraceptive method or be abstinent from heterosexual intercourse (as their preferred and usual lifestyle) during the intervention period and for at least 120 days after the last dose of pembrolizumab and at least 180 days after the last dose of enfortumab vedotin; whichever comes last. A female participant must agree not to donate eggs during this period as well.
• A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention.

Exclusion Criteria:

• Known additional non-urothelial 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 co-inhibitory 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 vaccine within 30 days prior to 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.
• History of 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Australia, Belgium, Canada, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Korea, Republic of, Mexico, Poland, Russian Federation, Spain, Sweden, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03924895
• Other Study ID Numbers: 3475-905; MK-3475-905 ( Other Identifier: Merck Protocol Number ); 2018-003809-26 ( Other Identifier: EudraCT Number ); KEYNOTE-905 ( Other Identifier: Merck ); EV-303 ( Other Identifier: Astellas Protocol Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Responsible Party: Merck Sharp & Dohme Corp.
• Study Sponsor: Merck Sharp & Dohme Corp.

Collaborators

• Seagen Inc.
• Astellas Pharma Global Development, Inc.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

• PRS Account: Merck Sharp & Dohme Corp.
• Verification Date: July 2021