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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 : December 11, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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 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).

Condition or disease Intervention/treatment Phase
High-risk Non-muscle Invasive Bladder Cancer Biological: Pembrolizumab Biological: BCG Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : December 10, 2018
Estimated Primary Completion Date : May 19, 2022
Estimated Study Completion Date : November 25, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: BCG plus Pembrolizumab (Arm 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).
Biological: Pembrolizumab
Pembrolizumab IV infusion of 200 mg Q3W
Other Name: KEYTRUDA®

Biological: BCG
BCG (intravesical instillation): 50 mg (wet weight) of powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy
Other Names:
  • TICE® BCG
  • OncoTICE®

Experimental: BCG (Arm 2)
Participants receive BCG monotherapy (Induction and Maintenance).
Biological: BCG
BCG (intravesical instillation): 50 mg (wet weight) of powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy
Other Names:
  • TICE® BCG
  • OncoTICE®




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Overall Survival (OS) [ 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) [ Time Frame: Up to ~5 years ]
    DSS is defined as the time from randomization to death due to bladder cancer.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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".

  17. 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".



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 evidence of 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

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): NCT03711032


Contacts
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
United States, Alaska
Alaska Urological Institute dba Alaska Clinical Research Center ( Site 1083) Recruiting
Anchorage, Alaska, United States, 99503
Contact: Study Coordinator    907-276-1455      
Spain
Hospital Universitario Quiron Madrid ( Site 0862) Recruiting
Pozuelo de Alarcon, Madrid, Spain, 28223
Contact: Study Coordinator    +34914521987      
Turkey
Eskisehir Osmangazi Universitesi Hastanesi ( Site 0953) Recruiting
Eskisehir, Turkey, 26480
Contact: Study Coordinator    +905327149696      
Necmettin Erbakan Universitesi Meram Tip Fakultesi Hastanesi ( Site 0961) Recruiting
Konya, Turkey, 42000
Contact: Study Coordinator    +905322679838      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03711032     History of Changes
Other Study ID Numbers: 3475-676
MK-3475-676 ( Other Identifier: Merck Protocol Number )
2018-001967-22 ( EudraCT Number )
First Posted: October 18, 2018    Key Record Dates
Last Update Posted: December 11, 2018
Last Verified: December 2018
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

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

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Pembrolizumab
BCG Vaccine
Antineoplastic Agents
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs