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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)

NCT03924856

Description:

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

Related Conditions:
  • Bladder Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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: 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-866
  • SECONDARY ID: 2018-003808-39
  • SECONDARY ID: MK-3475-866
  • SECONDARY ID: KEYNOTE-866
  • SECONDARY ID: 194870
  • NCT ID: NCT03924856

Conditions

  • Urinary Bladder Cancer, Muscle-invasive

Interventions

DrugSynonymsArms
PembrolizumabMK-3475Pembrolizumab + Gemcitabine + Cisplatin + Surgery
GemcitabinePembrolizumab + Gemcitabine + Cisplatin + Surgery
CisplatinPembrolizumab + Gemcitabine + Cisplatin + Surgery
PlaceboPlacebo + Gemcitabine + Cisplatin + Surgery

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + Gemcitabine + Cisplatin + SurgeryExperimentalParticipants received 4 preoperative cycles of pembrolizumab PLUS gemcitabine PLUS cisplatin, followed by surgery, followed by up to 13 cycles of postoperative pembrolizumab.
  • Pembrolizumab
  • Gemcitabine
  • Cisplatin
Placebo + Gemcitabine + Cisplatin + SurgeryPlacebo ComparatorParticipants 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.
  • Gemcitabine
  • Cisplatin
  • Placebo

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic Complete Response (pCR) Rate in All Participants
Time Frame:Up to approximately 4 months (Time of surgery)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall Survival (OS) in All Participants
Time Frame:Up to approximately 5.5 years
Safety Issue:
Description:Overall survival is defined as the time from randomization to death due to any cause.
Measure:Overall Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
Time Frame:Up to approximately 5.5 years
Safety Issue:
Description:Overall survival is defined as the time from randomization to death due to any cause.
Measure:Disease-Free Survival (DFS) in All Participants
Time Frame:From approximately 5 months up to approximately 5.5 years
Safety Issue:
Description: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
Measure:Disease-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
Time Frame:From approximately 5 months up to approximately 5.5 years
Safety Issue:
Description: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
Measure:Pathologic Downstaging (pDS) Rate in All Participants
Time Frame:Up to approximately 4 months (Time of surgery)
Safety Issue:
Description: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.
Measure:Pathologic Downstaging (pDS) Rate in Participants Whose Tumors Express PD-L1, CPS ≥10
Time Frame:Up to approximately 4 months (Time of surgery)
Safety Issue:
Description: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.
Measure:Number of Participants Experiencing Adverse Events (AEs)
Time Frame:Up to approximately 5.5 years
Safety Issue:
Description: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.
Measure:Number of Participants Discontinuing Study Drug Due to an AE
Time Frame:Up to approximately 1 year
Safety Issue:
Description: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.
Measure:Number of Participants Experiencing Perioperative Complications
Time Frame:Up to approximately 1 year
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure:Time to Deterioration (TTD) in the Total Score of FACT-G
Time Frame:Up to approximately 5.5 years
Safety Issue:
Description: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.
Measure:Time to Deterioration in EQ-5D-5L VAS
Time Frame:Up to approximately 5.5 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)
  • Pembrolizumab (MK-3475)
  • Chemotherapy

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