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

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ClinicalTrials.gov Identifier: NCT03924895
Recruitment Status : Recruiting
First Posted : April 23, 2019
Last Update Posted : August 8, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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).

Condition or disease Intervention/treatment Phase
Urinary Bladder Cancer, Muscle-invasive Drug: Pembrolizumab Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND]) Phase 3

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Study Type : Interventional
Estimated Enrollment : 610 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized Study of Cystectomy Plus Perioperative Pembrolizumab Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (KEYNOTE-905)
Actual Study Start Date : July 24, 2019
Estimated Primary Completion Date : February 12, 2025
Estimated Study Completion Date : February 16, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: Pembrolizumab + Surgery
Participants receive 3 preoperative cycles of pembrolizumab, followed by standard of care surgery, followed by up to 14 cycles of postoperative pembrolizumab.
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.

Active Comparator: Surgery alone
Participants receive standard of care surgery alone.
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.




Primary Outcome Measures :
  1. 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 (pT0) in examined tissue from RC and PLND, as determined centrally.

  2. 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.

  3. 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.

  4. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (≥50%) urothelial histology. Participants with mixed histology are eligible provided the urothelial component is ≥50%. Urothelial carcinomas not originating from the bladder are not eligible. Participants whose tumors contain any neuroendocrine component are not eligible.
  • 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 CrCl 30 to 59 mL/min
    • Eastern Cooperative Oncology Group (ECOG) Performance Status 2
    • Common Terminology Criteria for Adverse Events (CTCAE) v.4 Grade ≥2 audiometric hearing loss
    • CTCAE v.4 Grade ≥2 peripheral neuropathy
    • New York Heart Association (NYHA) Class III heart failure
  • Transurethral resection (TUR) of a bladder tumor that is submitted and adequate for evaluation of histology, muscle invasion and PD-L1 status
  • ECOG performance status of 0, 1, or 2
  • Adequate organ function

Exclusion Criteria:

  • Known additional non-urothelial malignancy that is progressing or has required active treatment ≤3 years of study randomization, with certain exceptions
  • Received any prior systemic anti-neoplastic treatment for muscle-invasive bladder cancer (MIBC)
  • Received prior therapy with a 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 anti-cancer therapy including investigational agents within 3 years prior to randomization
  • Received any prior radiotherapy to the bladder
  • Received a live vaccine within 30 days prior to the first dose of study drug
  • 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
  • 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
  • Hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
  • 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 (non-infectious) pneumonitis that required steroids, or current pneumonitis.
  • Active infection requiring systemic therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03924895


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

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Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03924895     History of Changes
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 )
First Posted: April 23, 2019    Key Record Dates
Last Update Posted: August 8, 2019
Last Verified: August 2019
Individual Participant Data (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

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

Keywords provided by Merck Sharp & Dohme Corp.:
Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Pembrolizumab (MK-3475)

Additional relevant MeSH terms:
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Sarcoma
Urinary Bladder Neoplasms
Muscle Neoplasms
Myosarcoma
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Soft Tissue Neoplasms
Muscular Diseases
Musculoskeletal Diseases
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Cisplatin
Pembrolizumab
Antineoplastic Agents
Antineoplastic Agents, Immunological