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Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) (MK-3475-676/KEYNOTE-676)

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ClinicalTrials.gov Identifier: NCT03711032
Recruitment Status : Recruiting
First Posted : October 18, 2018
Last Update Posted : November 27, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE October 15, 2018
First Posted Date  ICMJE October 18, 2018
Last Update Posted Date November 27, 2020
Actual Study Start Date  ICMJE December 24, 2018
Estimated Primary Completion Date May 19, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 11, 2020)
  • Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) (Cohort A) [ Time Frame: Up to ~3.5 years ]
    CRR is defined as the percentage of participants with CIS achieving a complete response (CR).
  • Event-Free Survival (EFS) (Cohort B) [ Time Frame: Up to ~5 years ]
    EFS is defined as the time from randomization until urothelial carcinoma (UC)-defined event, or death due to any cause.
Original Primary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) [ Time Frame: Up to ~3.5 years ]
CRR is defined as the percentage of participants with CIS achieving a complete response (CR).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 11, 2020)
  • EFS (Cohort A) [ Time Frame: Up to ~5 years ]
    EFS is defined as the time from randomization until UC-defined event, or death due to any cause.
  • Recurrence-Free Survival (RFS) (Cohorts A and B) [ Time Frame: Up to ~5 years ]
    RFS is defined as the time from randomization until the first occurrence of any UC recurrence, progression, or death due to any cause.
  • Overall Survival (OS) (Cohorts A and B) [ Time Frame: Up to ~5 years ]
    OS is defined as the time from randomization to death due to any cause.
  • Disease Specific Survival (DSS) (Cohorts A and B) [ Time Frame: Up to ~5 years ]
    DSS is defined as the time from randomization to death due to bladder cancer.
  • Time to Cystectomy (Cohorts A and B) [ Time Frame: Up to ~5 years ]
    Time to cystectomy is defined as the time from a participant's randomization until the date of cystectomy.
  • 12-Month EFS Rate (Cohort A) [ Time Frame: 12 months after EFS (up to ~5 years) ]
    EFS is defined as the time from randomization until UC-defined event, or death due to any cause. The 12-month EFS rate is defined as the percentage of participants with EFS at 12 months.
  • Duration of Response (DOR) (Cohorts A and B) [ Time Frame: Up to ~5 years ]
    DOR is defined as the time from first documented CR until end of response or death due to any cause, whichever occurs first.
  • 12-Month DOR Rate (Cohorts A and B) [ Time Frame: 12 months after CR (up to ~4.5 years) ]
    The 12-month DOR Rate is defined as the percentage of participants with a CR of at least 12 months duration.
  • Percentage of Participants Experiencing Adverse Events (AEs) (Cohorts A and B) [ Time Frame: Up to ~5 years ]
    An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.
  • Percentage of Participants Discontinuing Study Drug Due to AEs (Cohorts A and B) [ Time Frame: Up to ~5 years ]
    An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.
  • Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Cohorts A and B) [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. The change from baseline in Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score will be presented.
  • Change from Baseline in EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score (Cohorts A and B) [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented.
  • Change from Baseline in EORTC-QLQ-Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score (Cohorts A and B) [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EORTC-QLQ-NMIBC24 is a 24-item questionnaire developed to supplement the EORTC QLQ-C30 in high-risk NMIBC patients. Each item is scored out of 4 total points (1=Not at All to 4=Very Much). All responses are transformed from 0 to 100, with a high score indicating more symptoms or problems. The change from baseline in EORTC-QLQ-NMIBC24 total score will be presented.
  • Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) (Cohorts A and B) [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". The change from baseline in EQ-5D-5L VAS will be presented.
  • Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Cohorts A and B) [ Time Frame: Time of last PRO assessment (up to ~2 years) ]
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. TTD in Global Health Status/Quality of Life is defined as the time from baseline to the first onset of a 10 point or greater decrease from baseline in the Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score, with or without subsequent confirmation.
  • TTD in the EQ-5D-5L VAS (Cohorts A and B) [ Time Frame: Time of last PRO assessment (up to ~2 years) ]
    The EQ-5D-5L VAS records the respondent's self-rated health on a 20 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". TTD in EQ-5D-5L VAS is defined as the time from baseline to the first onset of a 7 point or greater decrease from baseline in EQ-5D-5L VAS, with or without subsequent confirmation, under a right-censoring rule.
  • CRR by BICR (Cohort B) [ Time Frame: Up to ~3.5 years ]
    CRR is defined as the percentage of participants with CIS achieving a CR.
  • 24-Month EFS Rate (Cohort B) [ Time Frame: 24 months after EFS (Up to ~5 years) ]
    EFS is defined as the time from randomization until UC-defined event, or death due to any cause. The 24-month EFS rate is defined as the percentage of participants with EFS at 24 months.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
  • Event-Free Survival (EFS) [ Time Frame: Up to ~5 years ]
    EFS is defined as the time from randomization until the reccurrence or progression of HR NMIBC, or death due to any cause.
  • Recurrence-Free Survival (RFS) [ Time Frame: Up to ~5 years ]
    RFS is defined as the time from randomization until the first occurrence of any urothelial carcinoma (UC) recurrence, or death due to any cause.
  • Overall Survival (OS) [ Time Frame: Up to ~5 years ]
    OS is defined as the time from randomization to death due to any cause.
  • Disease Specific Survival (DSS) [ Time Frame: Up to ~5 years ]
    DSS is defined as the time from randomization to death due to bladder cancer.
  • Time to Cystectomy [ Time Frame: Up to ~5 years ]
    Time to cystectomy is defined as the time from a participant's randomization until the date of cystectomy.
  • 12-Month EFS Rate [ Time Frame: 12 months after EFS (up to ~5 years) ]
    The 12-month EFS rate is defined as the probability of maintaining EFS at 12 months.
  • Duration of Response (DOR) [ Time Frame: Up to ~5 years ]
    DOR is defined as the time from first documented evidence of CR until disease progression or death due to any cause, whichever occurs first.
  • 12-Month DOR Rate [ Time Frame: 12 months after CR (up to ~4.5 years) ]
    The 12-month DOR Rate is defined as probability of maintaining DOR at 12 months.
  • Time to True Deterioration (TTD) in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) [ Time Frame: Time of last PRO assessment (up to ~2 years) ]
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Each item is scored out of 4 total points (1=Not at All to 4=Very Much. All responses are transformed from 0 to 100, with a high score indicating more symptoms or problems. TTD in EORTC-QLQ-C30 is defined as the time from baseline to the first onset of a 10 point or greater decrease from baseline in EORTC-QLQ-C30 score, with or without subsequent confirmation.
  • Percentage of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to ~5 years ]
    An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.
  • Percentage of Participants Discontinuing Study Drug Due to AEs [ Time Frame: Up to ~5 years ]
    An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.
  • Change From Baseline in EORTC-QLQ-C30 Global Health Status (Item 29) Scale Score [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Global Health Status (Item 29), participants are asked "How would you rate your overall health during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better level of function.
  • Change from Baseline in EORTC-QLQ-C30 Quality of Life (Item 30) Scale Score [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Quality of Life (Item 30), participants are asked "How would you rate your overall quality of life during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better level of function.
  • Change from Baseline in EORTC-QLQ-C30 Score [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Each item is scored out of 4 total points (1=Not at All to 4=Very Much. All responses are transformed from 0 to 100, with a high score indicating more symptoms or problems.
  • Change from Baseline in EORTC QLQ-Non-Muscle Invasive Bladder Cancer Module 24 (NMIBC24) Score [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EORTC-QLQ-NMIBC24 is a 24-item questionnaire developed to supplement the EORTC QLQ-C30 in high-risk NMIBC patients. Each item is scored out of 4 total points (1=Not at All to 4=Very Much). All responses are transformed from 0 to 100, with a high score indicating more symptoms or problems.
  • Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Index Score [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EQ-5D-5L assesses the 5 health state dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each health state dimension is rated separately on a five point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L health state dimensions are then converted to a single index score that ranges from 0 to 1, with 0 meaning "a health state as bad as being dead" and 1 representing "full health".
  • Change from Baseline in EuroQoL Visual Analogue Score (EQ VAS) [ Time Frame: Baseline, time of last PRO assessment (up to ~2 years) ]
    The EQ VAS records the respondent's self-rated health on a 20 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine".
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) (MK-3475-676/KEYNOTE-676)
Official Title  ICMJE A Phase 3, Randomized, Comparator-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in Participants With High-risk Non-muscle Invasive Bladder Cancer (HR NMIBC) That is Either Persistent or Recurrent Following BCG Induction or That is Naïve to BCG Treatment (KEYNOTE-676)
Brief Summary This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with BCG, compared to BCG monotherapy, in participants with HR NMIBC that is either persistent or recurrent following adequate BCG induction (Cohort A), or that is naïve to BCG treatment (Cohort B). The primary hypothesis for Cohort A is that the combination of pembrolizumab plus BCG has a superior complete response rate (CRR) as assessed by central pathology review compared to BCG in participants with carcinoma in situ (CIS). The primary hypothesis for Cohort B is that the combination of pembrolizumab plus BCG (either reduced maintenance or full maintenance) has a superior Event Free Survival (EFS) compared to BCG.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE High-risk Non-muscle Invasive Bladder Cancer
Intervention  ICMJE
  • Biological: Pembrolizumab
    Pembrolizumab IV infusion of 200 mg Q3W for BCG Post-Induction Cohort (Cohort A), or IV infusion of 400 mg Q6W for BCG Naïve Cohort (Cohort B), according to randomization
    Other Names:
    • KEYTRUDA®
    • MK-3475
  • Biological: BCG
    BCG (intravesical instillation): powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy
    Other Names:
    • TICE® BCG
    • OncoTICE®
Study Arms  ICMJE
  • Experimental: BCG plus Pembrolizumab: Post-induction Cohort A (Arm A-1)
    Participants receive BCG (Induction and Maintenance) in combination with 200 mg pembrolizumab administered intravenously (IV) every 3 weeks (Q3W) for 35 doses (~2 years).
    Interventions:
    • Biological: Pembrolizumab
    • Biological: BCG
  • Experimental: BCG Monotherapy: Post-induction Cohort A (Arm A-2)
    Participants receive BCG monotherapy (Induction and Maintenance).
    Intervention: Biological: BCG
  • Experimental: BCG plus Pembrolizumab: BCG Naïve Cohort B-Reduced Maintenance (Arm B-1)
    Participants receive BCG (Induction and reduced Maintenance) in combination with 400 mg pembrolizumab administered IV every 6 weeks (Q6W) for 9 doses (~1 year).
    Interventions:
    • Biological: Pembrolizumab
    • Biological: BCG
  • Experimental: BCG plus Pembrolizumab: BCG Naïve Cohort B-Full Maintenance (Arm B-2)
    Participants receive BCG (Induction and full Maintenance) in combination with 400 mg pembrolizumab administered IV Q6W for 9 doses (~1 year).
    Interventions:
    • Biological: Pembrolizumab
    • Biological: BCG
  • Experimental: BCG Monotherapy: BCG Naïve Cohort B (Arm B-3)
    Participants receive BCG monotherapy (Induction and Maintenance).
    Intervention: Biological: BCG
Publications * Kamat AM, Shore N, Hahn N, Alanee S, Nishiyama H, Shariat S, Nam K, Kapadia E, Frenkl T, Steinberg G. KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC. Future Oncol. 2020 Apr;16(10):507-516. doi: 10.2217/fon-2019-0817. Epub 2020 Mar 12.

*   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: November 11, 2020)
1525
Original Estimated Enrollment  ICMJE
 (submitted: October 16, 2018)
550
Estimated Study Completion Date  ICMJE November 25, 2024
Estimated Primary Completion Date May 19, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Has histologically-confirmed diagnosis of non-muscle invasive (T1, high grade Ta and/or CIS) UC of the bladder
  • Has undergone cystoscopy/ transurethral resection of bladder tumor (TURBT) to remove all resectable disease
  • Has provided tissue for biomarker analysis
  • Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
  • Has adequate organ function
  • During the treatment period and for ≥7 days after the last dose of BCG, male participants are EITHER abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent, OR, must agree to use contraception unless confirmed to be azoospermic
  • Female participants who are not pregnant, not breastfeeding, and either not a woman of child bearing potential (WOCBP); or are a WOCBP who agrees to use a contraception method that is highly effective or remains abstinent from heterosexual intercourse during the treatment period and for ≥7 days after the last dose of BCG or 120 days after the last dose of pembrolizumab, whichever comes last

BCG Post-induction Cohort (Cohort A) Only

  • Has been treated with one adequate course of BCG induction therapy for the treatment of HR NMIBC
  • Following adequate BCG induction therapy, must have persistent or recurrent HR NMIBC

Exclusion Criteria:

  • Has a history of or concurrent muscle invasive (i.e., T2, T3, T4) or metastatic UC
  • Has concurrent extra-vesical (ie, urethra, ureter, renal pelvis) non-muscle invasive urothelial carcinoma or invasive prostatic UC
  • Has received prior therapy with 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
  • Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks of start of study treatment
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of start of study treatment
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of start of study treatment
  • Has a known additional malignancy that is progressing or requires active treatment within the past 3 years
  • 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 one or more of the following contraindications to BCG: prior BCG sepsis or systemic infection, total bladder incontinence, or an adverse experience to a previous BCG instillation that resulted in treatment discontinuation and precludes retreating with BCG
  • Has an active infection requiring systemic therapy
  • Has a known history of human immunodeficiency virus (HIV) infection
  • Has a known history of Hepatitis B or known active Hepatitis C virus infection
  • Has current active tuberculosis
  • Has had an allogenic-tissue/solid organ transplant
  • Has any contraindication(s) to IV contrast or is otherwise unable to have computed tomography urothelial (CTU) imaging with IV contrast performed

BCG Post-induction Cohort (Cohort A) Only - Has persistent T1 disease following an induction course of BCG

BCG Naïve Cohort (Cohort B) Only

- Has received any prior treatment with BCG for their NMIBC within the past 2 years prior to study entry

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 Japan,   Australia,   Austria,   Belgium,   Canada,   Finland,   Germany,   Greece,   Italy,   Korea, Republic of,   Malaysia,   Netherlands,   Norway,   Peru,   Poland,   Portugal,   Spain,   Switzerland,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03711032
Other Study ID Numbers  ICMJE 3475-676
MK-3475-676 ( Other Identifier: Merck Protocol Number )
2018-001967-22 ( EudraCT Number )
194713 ( Other Identifier: JAPIC-CTI )
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 November 2020

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