Clinical Trials /

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)

NCT03711032

Description:

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 persistent or recurrent following adequate BCG induction. The primary hypothesis 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).

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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: 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 Persistent or Recurrent Following BCG Induction (KEYNOTE-676)

Clinical Trial IDs

  • ORG STUDY ID: 3475-676
  • SECONDARY ID: MK-3475-676
  • SECONDARY ID: 2018-001967-22
  • SECONDARY ID: 194713
  • NCT ID: NCT03711032

Conditions

  • High-risk Non-muscle Invasive Bladder Cancer

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®BCG plus Pembrolizumab (Arm 1)
BCGTICE® BCG, OncoTICE®BCG plus Pembrolizumab (Arm 1)

Purpose

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 persistent or recurrent following adequate BCG induction. The primary hypothesis 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).

Trial Arms

NameTypeDescriptionInterventions
BCG plus Pembrolizumab (Arm 1)ExperimentalParticipants receive BCG (Induction and Maintenance), in combination with 200 mg pembrolizumab administered intravenously (IV) every 3 weeks (Q3W) for 35 doses (~2 years).
  • Pembrolizumab
  • BCG
BCG (Arm 2)ExperimentalParticipants receive BCG monotherapy (Induction and Maintenance).
  • BCG

Eligibility Criteria

        Inclusion Criteria:

          -  Has histologically-confirmed diagnosis of non-muscle invasive (T1, high grade Ta
             and/or CIS) transitional cell carcinoma (TCC) of the bladder

          -  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

          -  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

          -  Male participants must agree to use approved contraception during the treatment period
             and for at least 120 days after the last dose of study treatment and refrain from
             donating sperm during this period

          -  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 approved
             contraception during the treatment period and for at least 120 days after the last
             dose of study treatment

        Exclusion Criteria:

          -  Has persistent T1 disease following an induction course of BCG

          -  Has a history of or concurrent muscle invasive (i.e., T2, T3, T4), locally advanced
             non-resectable or metastatic UC

          -  Has concurrent extra-vesical (i.e., urethra, ureter, renal pelvis) non-muscle invasive
             TCC of the urothelium, concurrent upper tract involvement, or invasive prostatic TCC
             including T1 or greater disease, or ductal invasion

          -  WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization

          -  Has received prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an
             agent directed to another 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

          -  Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 120 days
             after the last dose of trial treatment

          -  Has had an allogenic-tissue/solid organ transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response Rate (CRR) by Blinded Independent Central Review (BICR)
Time Frame:Up to ~3.5 years
Safety Issue:
Description:CRR is defined as the percentage of participants with CIS achieving a complete response (CR).

Secondary Outcome Measures

Measure:Event-Free Survival (EFS)
Time Frame:Up to ~5 years
Safety Issue:
Description:EFS is defined as the time from randomization until the recurrence or progression of HR NMIBC, or death due to any cause.
Measure:Recurrence-Free Survival (RFS)
Time Frame:Up to ~5 years
Safety Issue:
Description:RFS is defined as the time from randomization until the first occurrence of any urothelial carcinoma (UC) recurrence, or death due to any cause.
Measure:Overall Survival (OS)
Time Frame:Up to ~5 years
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Disease Specific Survival (DSS)
Time Frame:Up to ~5 years
Safety Issue:
Description:DSS is defined as the time from randomization to death due to bladder cancer.
Measure:Time to Cystectomy
Time Frame:Up to ~5 years
Safety Issue:
Description:Time to cystectomy is defined as the time from a participant's randomization until the date of cystectomy.
Measure:12-Month EFS Rate
Time Frame:12 months after EFS (up to ~5 years)
Safety Issue:
Description:The 12-month EFS rate is defined as the percentage of participants with EFS at 12 months.
Measure:Duration of Response (DOR)
Time Frame:Up to ~5 years
Safety Issue:
Description:DOR is defined as the time from first documented CR until end of response or death due to any cause, whichever occurs first.
Measure:12-Month DOR Rate
Time Frame:12 months after CR (up to ~4.5 years)
Safety Issue:
Description:The 12-month DOR Rate is defined as the percentage of participants with a CR of at least 12 months duration.
Measure:Percentage of Participants Experiencing Adverse Events (AEs)
Time Frame:Up to ~5 years
Safety Issue:
Description: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.
Measure:Percentage of Participants Discontinuing Study Drug Due to AEs
Time Frame:Up to ~5 years
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline, time of last PRO assessment (up to ~2 years)
Safety Issue:
Description: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.
Measure:Change from Baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) Combined Score
Time Frame:Baseline, time of last PRO assessment (up to ~2 years)
Safety Issue:
Description: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.
Measure:Change from Baseline in EORTC QLQ-Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score
Time Frame:Baseline, time of last PRO assessment (up to ~2 years)
Safety Issue:
Description: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.
Measure:Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS)
Time Frame:Baseline, time of last PRO assessment (up to ~2 years)
Safety Issue:
Description: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.
Measure:Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
Time Frame:Time of last PRO assessment (up to ~2 years)
Safety Issue:
Description: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.
Measure:Time to Deterioration (TTD) in the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS)
Time Frame:Time of last PRO assessment (up to ~2 years)
Safety Issue:
Description: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.

Details

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

Trial Keywords

  • programmed cell death receptor 1 (PD-1)
  • programmed cell death ligand 1 (PD-L1)
  • anti-PD-1
  • anti-PD-L1
  • BCG
  • HR NMIBC
  • Patient Reported Outcome (PRO)

Last Updated

December 22, 2019