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Active, Not Recruiting

NCT Number: NCT03711032

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)

Researchers are looking for new ways to treat high-risk non muscle invasive bladder cancer (HR NMIBC). NMIBC is cancer in the tissue that lines the inside of the bladder but has not spread to the bladder muscle or outside of the bladder. High-risk means NMIBC may have a high chance of getting worse or coming back after treatment.

The goals of this study are to learn: 1. If more people who receive pembrolizumab with Bacillus Calmette-Guerin (BCG) have no signs of cancer in their body and live longer without the cancer growing, spreading, or coming back compared to people who receive BCG alone. 2. About the safety and how well people tolerate BCG alone or in combination with pembrolizumab.

Active, Not Recruiting

This study is active but is not currently recruiting participants.

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Key information

Conditions

High-Risk Non-Muscle Invasive Bladder Cancer Parkinson Disease 4, Autosomal Dominant Lewy Body

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

GenesisCare North Shore ( Site 0010), St Leonards, New South Wales, Australia

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Have locally and blinded independent central review (BICR)-confirmed histological diagnosis of high-risk 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 locally advanced (i.e., T2, T3, T4) or metastatic UC
  • Has concurrent extra-vesical (i.e, urethra, ureter, renal pelvis) non-muscle invasive urothelial carcinoma or a history of extra-vesical non-muscle invasive 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/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
  • 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 or diagnosis requiring systemic antimicrobial 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 screening 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

Treatment and study plan

Pembrolizumab

Biological

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

BCG

Biological

BCG (intravesical instillation): powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy

Other names: TICE® BCG, OncoTICE®

Primary outcomes

  1. 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 carcinoma in situ (CIS) achieving a complete response (CR).

  2. 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.

Secondary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Duration of Response (DOR) (Cohorts A and B)

    Time frame: Up to ~5 years

    DOR in participants with CIS is defined as the time from first documented CR until end of response or death due to any cause, whichever occurs first.

  8. 12-Month DOR Rate (Cohorts A and B)

    Time frame: 12 months after CR (up to ~4.5 years)

    The 12-month DOR Rate in participants with CIS is defined as the percentage of participants with a CR of at least 12 months duration.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study title

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)

Important dates

Study start
2018
Primary completion
2026
Study completion
2034
First posted
Oct 18, 2018
Registry last updated
May 1, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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