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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 : February 21, 2021
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 : 870 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 : June 15, 2025
Estimated Study Completion Date : June 15, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

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 [ Time Frame: Up to approximately 15 Weeks (Time of surgery) ]
    pCR rate is defined as the percentage of participants having pCR. pCR is defined as absence of viable tumor (pT0pT0N0) in examined tissue from RC and PLND, as assessed by blinded independent central review (BICR).

  2. Event-Free Survival (EFS) [ Time Frame: Up to approximately 71 months ]
    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 BICR assessments, or death due to any cause.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Up to approximately 71 months ]
    Overall survival is defined as the time from randomization to death due to any cause.

  2. Disease-Free Survival (DFS) [ Time Frame: From approximately 20 weeks up to approximately 71 months ]
    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 computerized tomography (CT) or magnetic resonance imaging (MRI) by BICR and or biopsy or death from any cause.

  3. Pathologic Downstaging (pDS) Rate [ Time Frame: Up to approximately 15 Weeks (Time of surgery) ]
    pDS 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 plus PLND as assessed by BICR.

  4. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 71 months ]
    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.

  5. Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 12 months ]
    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.

  6. Number of Participants Who Experienced Perioperative Complications [ Time Frame: Up to approximately 12 months ]
    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.

  7. Change in Patient-Reported Outcomes from Baseline in Total Score of Functional Assessment of Cancer Therapy - General (FACT-G) [ Time Frame: Baseline, Up to approximately 71 months ]
    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.

  8. Change in Patient-Reported Outcomes from Baseline in Total Score of FACT-Bladder- (FACT-BI-Cys) [ Time Frame: Baseline, Up to approximately 71 months ]
    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.

  9. Change in Patient-Reported Outcomes from Baseline in FACT-BI-Cys-Trial Outcome Index (TOI) [ Time Frame: Baseline, Up to approximately 71 months ]
    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.

  10. Change in Patient-Reported Outcomes from Baseline in EuroQol Five-Dimensional Questionnaire (EQ-5D-5L) Visual Analog Score (VAS) [ Time Frame: Baseline, Up to approximately 71 months ]
    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.

  11. Time to Deterioration (TTD) in the Total Score of FACT-G [ Time Frame: Up to approximately 71 months ]
    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.

  12. TTD in EQ-5D-5L VAS [ Time Frame: Up to approximately 71 months ]
    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.



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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 urothelial carcinoma (UC) / muscle invasive bladder cancer (MIBC) (T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology
  • Have clinically non-metastatic bladder cancer (N≤1 M0) determined by imaging (computed tomography (CT) or magnetic resonance imaging (MRI) of the chest/abdomen/pelvis
  • Be deemed eligible for Radical Cystectomy (RC) + Pelvic Lymph Node Dissection (PLND)
  • Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Have adequate organ function
  • Male and female participants are eligible to participate if they agree to the contraception use as per study protocol

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 treatment for MIBC or non-invasive muscle bladder cancer (NMIBC - prior treatment for NMIBC with intravesical BCG/chemotherapy is permitted) or prior therapy with an anti- programmed cell death 1 (PD-1), anti-programmed cell death ligand 1/ ligand 2 (PD-L1/L2), or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
  • Has ≥N2 disease or metastatic disease (M1) as identified by imaging
  • Is cisplatin-ineligible, as defined by meeting any one of the cisplatin ineligibility criteria as per protocol
  • Has received prior systemic anticancer therapy including investigational agents within 3 years of randomization or any radiotherapy to the bladder
  • Has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC
  • Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention
  • Has a diagnosis of immunodeficiency or has a known history of human immunodeficiency virus (HIV) infection, Hepatitis B infection or known active Hepatitis C infection
  • Has a known psychiatric or substance abuse disorder
  • Has had an allogenic tissue/solid organ transplant

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
Show Show 174 study locations
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
Additional Information:
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03924856    
Other Study ID Numbers: 3475-866
2018-003808-39 ( EudraCT Number )
MK-3475-866 ( Other Identifier: Merck Protocol Number )
KEYNOTE-866 ( Other Identifier: Merck )
194870 ( Registry Identifier: JAPIC-CTI )
First Posted: April 23, 2019    Key Record Dates
Last Update Posted: February 21, 2021
Last Verified: February 2021
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
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Soft Tissue Neoplasms
Muscular Diseases
Musculoskeletal Diseases
Gemcitabine
Cisplatin
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