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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)

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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.

Tracking Information
First Submitted Date  ICMJE April 22, 2019
First Posted Date  ICMJE April 23, 2019
Last Update Posted Date July 12, 2019
Actual Study Start Date  ICMJE June 13, 2019
Estimated Primary Completion Date January 15, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
  • 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.
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 22, 2019)
  • Pathologic Complete Response (pCR) Rate in All Participants [ Time Frame: Up to approximately 4 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 4 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.
Change History Complete list of historical versions of study NCT03924856 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 22, 2019)
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE 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)
Brief Summary A global study to evaluate peri-operative pembrolizumab with chemotherapy versus placebo to pembrolizumab plus chemotherapy in cisplatin eligible patients.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Double-blind
Primary Purpose: Treatment
Condition  ICMJE Urinary Bladder Cancer, Muscle-invasive
Intervention  ICMJE
  • 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.
  • Drug: Placebo
    Placebo to pembrolizumab by IV infusion, given on Day 1 of each 21-day cycle
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Pembrolizumab
    • Drug: Gemcitabine
    • Drug: Cisplatin
    • Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
  • 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.
    Interventions:
    • Drug: Gemcitabine
    • Drug: Cisplatin
    • Procedure: Surgery (radical cystectomy (RC) plus Pelvic Lymph Node Dissection [PLND])
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 22, 2019)
790
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 15, 2025
Estimated Primary Completion Date January 15, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Australia,   Israel,   Korea, Republic of,   Poland,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03924856
Other Study ID Numbers  ICMJE 3475-866
2018-003808-39 ( EudraCT Number )
MK-3475-866 ( Other Identifier: Merck Protocol Number )
KEYNOTE-866 ( Other Identifier: Merck )
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  ICMJE
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  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP