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Perioperative Pembrolizumab (MK-3475) Plus Neoadjuvant Chemotherapy Versus Perioperative Placebo Plus Neoadjuvant Chemotherapy for Cisplatin-eligible Muscle-invasive Bladder Cancer (MIBC) (MK-3475-866/KEYNOTE-866) (KEYNOTE-866)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03924856
Recruitment Status : Recruiting
First Posted : April 23, 2019
Last Update Posted : July 12, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
A global study to evaluate peri-operative pembrolizumab with chemotherapy versus placebo to pembrolizumab plus chemotherapy in cisplatin eligible patients.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 790 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-blind Study to Evaluate Perioperative Pembrolizumab (MK-3475) + Neoadjuvant Chemotherapy Versus Perioperative Placebo + Neoadjuvant Chemotherapy in Cisplatin-eligible Participants With Muscle-invasive Bladder Cancer (KEYNOTE-866)
Actual Study Start Date : June 13, 2019
Estimated Primary Completion Date : January 15, 2025
Estimated Study Completion Date : January 15, 2025


Arm Intervention/treatment
Experimental: Pembrolizumab + Gemcitabine + Cisplatin + Surgery
Participants received 4 preoperative cycles of pembrolizumab PLUS gemcitabine PLUS cisplatin, followed by surgery, followed by up to 13 cycles of postoperative pembrolizumab.
Drug: Pembrolizumab
Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle
Other Name: MK-3475

Drug: Gemcitabine
Gemcitabine 1000 mg/m^2, IV infusion on Days 1 and 8 of each 21-day cycle

Drug: Cisplatin
Cisplatin 70 mg/m^2, IV infusion 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.

Placebo Comparator: Placebo + Gemcitabine + Cisplatin + Surgery
Participants received 4 preoperative cycles of placebo to pembrolizumab PLUS gemcitabine PLUS cisplatin, followed by surgery, followed by up to 13 cycles of postoperative placebo to pembrolizumab.
Drug: Gemcitabine
Gemcitabine 1000 mg/m^2, IV infusion on Days 1 and 8 of each 21-day cycle

Drug: Cisplatin
Cisplatin 70 mg/m^2, IV infusion 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: Placebo
Placebo to pembrolizumab by IV infusion, given on Day 1 of each 21-day cycle




Primary Outcome Measures :
  1. Pathologic Complete Response (pCR) Rate in All Participants [ Time Frame: Up to approximately 4 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 4 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 5.5 years ]
    Overall survival 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 5.5 years ]
    Overall survival is defined as the time from randomization to death due to any cause.

  3. Disease-Free Survival (DFS) in All Participants [ Time Frame: From approximately 5 months up to approximately 5.5 years ]

    DFS is defined as the time from post-surgery baseline scan until the first occurrence of either:

    • Local or distant recurrence as assessed by CT or MRI (BICR) and/or biopsy
    • Death from any cause

  4. Disease-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10 [ Time Frame: From approximately 5 months up to approximately 5.5 years ]

    DFS is defined as the time from post-surgery baseline scan until the first occurrence of either:

    • Local or distant recurrence as assessed by CT or MRI (BICR) and/or biopsy
    • Death from any cause

  5. Pathologic Downstaging (pDS) Rate in All Participants [ Time Frame: Up to approximately 4 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 4 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 5.5 years ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.

  8. Number of Participants Discontinuing Study Drug Due to an AE [ Time Frame: Up to approximately 1 year ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.

  9. Number of Participants Experiencing Perioperative Complications [ Time Frame: Up to approximately 1 year ]
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.

  10. Change in Patient-Reported Outcomes from Baseline in Total Score of Functional Assessment of Cancer Therapy - General (FACT-G) [ Time Frame: Baseline and time of last patient-reported outcome assessment (up to approximately 5.5 years) ]
    The FACT-G is a health-related quality of life (HRQoL) 27-item questionnaire in patients being treated for cancer. The FACT-G subscales include Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB), and Functional Well-Being (FWB). All items are scored on a 5-point Likert scale of 0 to 4, with higher scores indicating higher HRQoL. The total score can range from 0 to 108.

  11. Change in Patient-Reported Outcomes from Baseline in Total Score of Functional Assessment of Cancer Therapy-Bladder Cancer-Specific Subscale/Symptom Index for Participants Undergoing Cystectomy (Total Score FACT BI-Cys) [ Time Frame: Baseline and time of last patient-reported outcome assessment (up to approximately 5.5 years) ]
    Total Score of FACT BI-Cys is the sum of FACT-G total score and FACT-Bl-Cys score. FACT-Bl-Cys contains 17 items on the bowel, bladder, and sexual symptoms following cystectomy. The FACT-G is a health-related quality of life (HRQoL) 27-item questionnaire in patients being treated for cancer. The FACT-G subscales include Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB), and Functional Well-Being (FWB). All items are scored on a 5-point Likert scale of 0 to 4, with higher scores indicating higher HRQoL. The total score of FACT-Bl-Cys can range from 0 to 168.

  12. Change in Patient-Reported Outcomes from Baseline in FACT-Bl-Cys-Trial Outcome Index (TOI) [ Time Frame: Baseline and time of last patient-reported outcome assessment (up to approximately 5.5 years) ]
    FACT-Bl-Cys Trial Outcome Index (TOI) is the sum of FACT-G PWB score, FWB score, and FACT-Bl-Cys score. FACT-Bl-Cys contains 17 items on the bowel, bladder, and sexual symptoms following cystectomy. The FACT-G is a health-related quality of life (HRQoL) 27-item questionnaire in patients being treated for cancer. The FACT-G subscales include Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB), and Functional Well-Being (FWB). All items are scored on a 5-point Likert scale of 0 to 4, with higher scores indicating higher HRQoL. The total score of FACT-Bl-Cys TOI can range from 0 to 116.

  13. Change in Patient-Reported Outcomes from Baseline in EuroQol Five-Dimensional Questionnaire (EQ-5D-5L) Visual Analog Score (VAS) [ Time Frame: Baseline and time of last patient-reported outcome assessment (up to approximately 5.5 years) ]
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. In the EQ-5D-5L VAS, the participant rates his or her general state of health at the time of the assessment on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.

  14. Change in Patient-Reported Outcomes from Baseline in EQ-5D-5L Utility Score [ Time Frame: Baseline and time of last patient-reported outcome assessment (up to approximately 5.5 years) ]
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and includes 5 health state dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems), for a total range of 5 to 25 points, with a lower score indicating a better health outcome.

  15. Time to Deterioration (TTD) in the Total Score of FACT-G [ Time Frame: Up to approximately 5.5 years ]
    The FACT-G is a health-related quality of life (HRQoL) 27-item questionnaire in patients being treated for cancer. The FACT-G subscales include Physical Well-Being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB), and Functional Well-Being (FWB). All items are scored on a 5-point Likert scale of 0-4, with higher scores indicating higher HRQoL. TTD is defined as the time from baseline to the first onset of patient-reported outcomes (PRO) deterioration. For the FACT-G questionnaire, deteriorations are defined as a decrease of 7 points or more (out of 108) from baseline in total score.

  16. Time to Deterioration in EQ-5D-5L VAS [ Time Frame: Up to approximately 5.5 years ]
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and includes 5 health state dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In the EQ-5D-5L VAS, the participant rates his or her general state of health at the time of the assessment on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. TTD is defined as the time from baseline to the first onset of PRO deterioration. For the EQ 5D-5L, deterioration is defined as a decrease of 7 points or more from baseline in the VAS.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

- Have a histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (≥50%) urothelial histology (histology and presence of muscle invasion to be confirmed by BICR): Participants with mixed histology are eligible provided the urothelial component is ≥50%.

Participants whose tumors contain any neuroendocrine component are not eligible.

Urothelial carcinomas not originating from the bladder (e.g., upper tract [ureters, renal pelvis], urethra) are not eligible.

  • Have clinically non-metastatic bladder cancer (N0M0) determined by imaging (computed tomography (CT) chest or magnetic resonance imaging (MRI) of the abdomen/pelvis.
  • 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).
  • Have a transurethral resection (TUR) of a bladder tumor that is submitted and adequate to determine histology, muscle invasion, and PD-L1 status by central pathology vendor.
  • Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Have demonstrated adequate organ function.

Exclusion Criteria:

  • Has a known additional malignancy that is progressing or has required active anti-cancer treatment ≤3 years of study randomization with certain exceptions.
  • Has received any prior systemic anti-neoplastic treatment for MIBC.
  • Is cisplatin-ineligible, as defined by meeting any one of the study criteria.
  • 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 co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
  • Has received therapy with hematopoietic growth factor such as granulocyte-colony stimulating factor (G-CSF) or granulocyte-monocyte-colony stimulating factor(GM-CSF) in 14 days prior to randomization.
  • Has received prior systemic anti-cancer therapy including investigational agents within 3 years of randomization.
  • Has received any prior radiotherapy to the bladder.
  • Has received a live vaccine within 30 days prior to the first dose of study drug.
  • 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.
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
  • Has hypersensitivity to monoclonal antibodies (mAbs, including pembrolizumab) and/or any of their excipients.
  • Has severe hypersensitivity (≥Grade 3) to cisplatin and/or gemcitabine and any of their excipients.
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  • Has an 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): NCT03924856


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

Locations
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United States, Indiana
Parkview Cancer Institute ( Site 0077) Recruiting
Fort Wayne, Indiana, United States, 46845
Contact: Study Coordinator    260-266-9167      
United States, Maine
New England Cancer Specialists ( Site 0070) Recruiting
Scarborough, Maine, United States, 04074
Contact: Study Coordinator    207-303-3423      
United States, Oklahoma
Oklahoma Cancer Specialists and Research Institute, LLC ( Site 0021) Recruiting
Tulsa, Oklahoma, United States, 74146
Contact: Study Coordinator    918-505-3200      
United States, Washington
Northwest Medical Specialties, PLLC ( Site 0061) Recruiting
Tacoma, Washington, United States, 98405
Contact: Study Coordinator    253-428-8753      
Australia, New South Wales
Southside Cancer Care Centre ( Site 1252) Recruiting
Sydney, New South Wales, Australia, 2228
Contact: Study Coordinator    +61285569300      
Australia, Victoria
Peninsula Health Frankston Hospital ( Site 1258) Recruiting
Frankston, Victoria, Australia, 3199
Contact: Study Coordinator    +61397848520      
Israel
Rabin Medical Center ( Site 0804) Recruiting
Petach Tikva, Israel, 4941492
Contact: Study Coordinator    +97239378074      
Sheba Medical Center ( Site 0801) Recruiting
Ramat Gan, Israel, 5265601
Contact: Study Coordinator    +97235302191      
Sourasky Medical Center ( Site 0807) Recruiting
Tel Aviv, Israel, 6423906
Contact: Study Coordinator    +97236973413      
Korea, Republic of
Seoul National University Bundang Hospital ( Site 1356) Recruiting
Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620
Contact: Study Coordinator    +82317877351      
Seoul National University Hospital ( Site 1352) Recruiting
Seoul, Korea, Republic of, 03080
Contact: Study Coordinator    +82220720361      
Samsung Medical Center ( Site 1353) Recruiting
Seoul, Korea, Republic of, 06351
Contact: Study Coordinator    +82234103557      
Poland
Beskidzkie Centrum Onkologii im. Jana Pawla II ( Site 1060) Recruiting
Bielsko-Biala, Poland, 43-300
Contact: Study Coordinator    +48606399091      
Centrum Onkologii im.prof. F. Lukaszczyka w Bydgoszczy ( Site 1068) Recruiting
Bydgoszcz, Poland, 85-796
Contact: Study Coordinator    +48501446778      
Europejskie Centrum Zdrowia Otwock ( Site 1057) Recruiting
Otwock, Poland, 05-400
Contact: Study Coordinator    +48601200599      
Magodent Szpital Elblaska ( Site 1051) Recruiting
Warszawa, Poland, 01-748
Contact: Study Coordinator    +48691666578      
Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego ( Site 1062) Recruiting
Wroclaw, Poland, 50-556
Contact: Study Coordinator    +48601143281      
Spain
Hospital Universitario Quiron Madrid ( Site 0657) Recruiting
Pozuelo de Alarcon, Madrid, Spain, 28223
Contact: Study Coordinator    +34914521987      
Hospital del Mar ( Site 0653) Recruiting
Barcelona, Spain, 08003
Contact: Study Coordinator    +34932483139      
H. de Gerona Dr. Josep Trueta ( Site 0651) Recruiting
Girona, Spain, 17007
Contact: Study Coordinator    +349722258284028      
Hospital Universitario Ramon y Cajal ( Site 0660) Recruiting
Madrid, Spain, 28034
Contact: Study Coordinator    +34913368263      
Hospital Universitario San Carlos ( Site 0663) Recruiting
Madrid, Spain, 28040
Contact: Study Coordinator    +349133030007554      
Hospital Universitario La Paz ( Site 0661) Recruiting
Madrid, Spain, 28046
Contact: Study Coordinator    +34912071138      
Hospital Nuestra Sra. de Valme ( Site 0658) Recruiting
Sevilla, Spain, 41014
Contact: Study Coordinator    +34955015000      
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: NCT03924856     History of Changes
Other Study ID Numbers: 3475-866
2018-003808-39 ( EudraCT Number )
MK-3475-866 ( Other Identifier: Merck Protocol Number )
KEYNOTE-866 ( Other Identifier: Merck )
First Posted: April 23, 2019    Key Record Dates
Last Update Posted: July 12, 2019
Last Verified: July 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)
Chemotherapy

Additional relevant MeSH terms:
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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
Sarcoma
Cisplatin
Gemcitabine
Pembrolizumab
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological