The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03711032




Registration number
NCT03711032
Ethics application status
Date submitted
15/10/2018
Date registered
18/10/2018

Titles & IDs
Public 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)
Scientific 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)
Secondary ID [1] 0 0
MK-3475-676
Secondary ID [2] 0 0
3475-676
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High-risk Non-muscle Invasive Bladder Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bladder - transitional cell cancer
Renal and Urogenital 0 0 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Pembrolizumab
Treatment: Other - BCG

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).

Experimental: BCG Monotherapy: Post-induction Cohort A (Arm A-2) - Participants receive BCG monotherapy (Induction and Maintenance).

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).

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).

Experimental: BCG Monotherapy: BCG Naïve Cohort B (Arm B-3) - Participants receive BCG monotherapy (Induction and Maintenance).


Treatment: Other: 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

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

Intervention code [1] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) (Cohort A)
Timepoint [1] 0 0
Up to ~3.5 years
Primary outcome [2] 0 0
Event-Free Survival (EFS) (Cohort B)
Timepoint [2] 0 0
Up to ~5 years
Secondary outcome [1] 0 0
EFS (Cohort A)
Timepoint [1] 0 0
Up to ~5 years
Secondary outcome [2] 0 0
Recurrence-Free Survival (RFS) (Cohorts A and B)
Timepoint [2] 0 0
Up to ~5 years
Secondary outcome [3] 0 0
Overall Survival (OS) (Cohorts A and B)
Timepoint [3] 0 0
Up to ~5 years
Secondary outcome [4] 0 0
Disease Specific Survival (DSS) (Cohorts A and B)
Timepoint [4] 0 0
Up to ~5 years
Secondary outcome [5] 0 0
Time to Cystectomy (Cohorts A and B)
Timepoint [5] 0 0
Up to ~5 years
Secondary outcome [6] 0 0
12-Month EFS Rate (Cohort A)
Timepoint [6] 0 0
12 months after EFS (up to ~5 years)
Secondary outcome [7] 0 0
Duration of Response (DOR) (Cohorts A and B)
Timepoint [7] 0 0
Up to ~5 years
Secondary outcome [8] 0 0
12-Month DOR Rate (Cohorts A and B)
Timepoint [8] 0 0
12 months after CR (up to ~4.5 years)
Secondary outcome [9] 0 0
Percentage of Participants Experiencing Adverse Events (AEs) (Cohorts A and B)
Timepoint [9] 0 0
Up to ~5 years
Secondary outcome [10] 0 0
Percentage of Participants Discontinuing Study Drug Due to AEs (Cohorts A and B)
Timepoint [10] 0 0
Up to ~5 years
Secondary outcome [11] 0 0
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)
Timepoint [11] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [12] 0 0
Change from Baseline in EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score (Cohorts A and B)
Timepoint [12] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [13] 0 0
Change from Baseline in EORTC-QLQ-Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score (Cohorts A and B)
Timepoint [13] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [14] 0 0
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)
Timepoint [14] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [15] 0 0
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)
Timepoint [15] 0 0
Time of last PRO assessment (up to ~2 years)
Secondary outcome [16] 0 0
TTD in the EQ-5D-5L VAS (Cohorts A and B)
Timepoint [16] 0 0
Time of last PRO assessment (up to ~2 years)
Secondary outcome [17] 0 0
CRR by BICR (Cohort B)
Timepoint [17] 0 0
Up to ~3.5 years
Secondary outcome [18] 0 0
24-Month EFS Rate (Cohort B)
Timepoint [18] 0 0
24 months after EFS (Up to ~5 years)

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
GenesisCare North Shore ( Site 0010) - St Leonards
Recruitment hospital [2] 0 0
Northern Cancer Institute. ( Site 0003) - St Leonards
Recruitment hospital [3] 0 0
Sydney Adventist Hospital ( Site 0001) - Wahroonga
Recruitment hospital [4] 0 0
Epworth Hospital ( Site 0009) - Richmond
Recruitment postcode(s) [1] 0 0
2065 - St Leonards
Recruitment postcode(s) [2] 0 0
2076 - Wahroonga
Recruitment postcode(s) [3] 0 0
3121 - Richmond
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alaska
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Colorado
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Georgia
Country [7] 0 0
United States of America
State/province [7] 0 0
Illinois
Country [8] 0 0
United States of America
State/province [8] 0 0
Kansas
Country [9] 0 0
United States of America
State/province [9] 0 0
Louisiana
Country [10] 0 0
United States of America
State/province [10] 0 0
Michigan
Country [11] 0 0
United States of America
State/province [11] 0 0
New Jersey
Country [12] 0 0
United States of America
State/province [12] 0 0
New York
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Oregon
Country [15] 0 0
United States of America
State/province [15] 0 0
Pennsylvania
Country [16] 0 0
United States of America
State/province [16] 0 0
South Carolina
Country [17] 0 0
United States of America
State/province [17] 0 0
Tennessee
Country [18] 0 0
United States of America
State/province [18] 0 0
Texas
Country [19] 0 0
United States of America
State/province [19] 0 0
Vermont
Country [20] 0 0
United States of America
State/province [20] 0 0
Virginia
Country [21] 0 0
Austria
State/province [21] 0 0
Oberosterreich
Country [22] 0 0
Austria
State/province [22] 0 0
Tirol
Country [23] 0 0
Austria
State/province [23] 0 0
Wien
Country [24] 0 0
Austria
State/province [24] 0 0
Salzburg
Country [25] 0 0
Belgium
State/province [25] 0 0
Antwerpen
Country [26] 0 0
Belgium
State/province [26] 0 0
Namur
Country [27] 0 0
Belgium
State/province [27] 0 0
Oost-Vlaanderen
Country [28] 0 0
Brazil
State/province [28] 0 0
Ceara
Country [29] 0 0
Brazil
State/province [29] 0 0
Parana
Country [30] 0 0
Brazil
State/province [30] 0 0
Sao Paulo
Country [31] 0 0
Canada
State/province [31] 0 0
British Columbia
Country [32] 0 0
Canada
State/province [32] 0 0
New Brunswick
Country [33] 0 0
Canada
State/province [33] 0 0
Ontario
Country [34] 0 0
Canada
State/province [34] 0 0
Quebec
Country [35] 0 0
China
State/province [35] 0 0
Beijing
Country [36] 0 0
China
State/province [36] 0 0
Chongqing
Country [37] 0 0
China
State/province [37] 0 0
Fujian
Country [38] 0 0
China
State/province [38] 0 0
Guangdong
Country [39] 0 0
China
State/province [39] 0 0
Heilongjiang
Country [40] 0 0
China
State/province [40] 0 0
Henan
Country [41] 0 0
China
State/province [41] 0 0
Hubei
Country [42] 0 0
China
State/province [42] 0 0
Hunan
Country [43] 0 0
China
State/province [43] 0 0
Jiangsu
Country [44] 0 0
China
State/province [44] 0 0
Shaanxi
Country [45] 0 0
China
State/province [45] 0 0
Sichuan
Country [46] 0 0
China
State/province [46] 0 0
Tianjin
Country [47] 0 0
China
State/province [47] 0 0
Zhejiang
Country [48] 0 0
Colombia
State/province [48] 0 0
Antioquia
Country [49] 0 0
Colombia
State/province [49] 0 0
Cordoba
Country [50] 0 0
Colombia
State/province [50] 0 0
Distrito Capital De Bogota
Country [51] 0 0
Colombia
State/province [51] 0 0
Risaralda
Country [52] 0 0
Colombia
State/province [52] 0 0
Valle Del Cauca
Country [53] 0 0
Costa Rica
State/province [53] 0 0
San Jose
Country [54] 0 0
Finland
State/province [54] 0 0
Pirkanmaa
Country [55] 0 0
France
State/province [55] 0 0
Bourgogne
Country [56] 0 0
France
State/province [56] 0 0
Hauts-de-Seine
Country [57] 0 0
France
State/province [57] 0 0
Ille-et-Vilaine
Country [58] 0 0
France
State/province [58] 0 0
Nord
Country [59] 0 0
France
State/province [59] 0 0
Seine-et-Marne
Country [60] 0 0
Germany
State/province [60] 0 0
Bayern
Country [61] 0 0
Germany
State/province [61] 0 0
Rheinland-Pfalz
Country [62] 0 0
Germany
State/province [62] 0 0
Thuringen
Country [63] 0 0
Greece
State/province [63] 0 0
Achaia
Country [64] 0 0
Greece
State/province [64] 0 0
Attiki
Country [65] 0 0
Greece
State/province [65] 0 0
Kentriki Makedonia
Country [66] 0 0
Greece
State/province [66] 0 0
Thessalia
Country [67] 0 0
Guatemala
State/province [67] 0 0
Guatemala City
Country [68] 0 0
Guatemala
State/province [68] 0 0
Guatemala
Country [69] 0 0
Hungary
State/province [69] 0 0
Baranya
Country [70] 0 0
Hungary
State/province [70] 0 0
Csongrad
Country [71] 0 0
Hungary
State/province [71] 0 0
Budapest
Country [72] 0 0
Hungary
State/province [72] 0 0
Debrecen
Country [73] 0 0
Italy
State/province [73] 0 0
Abruzzo
Country [74] 0 0
Italy
State/province [74] 0 0
Milano
Country [75] 0 0
Italy
State/province [75] 0 0
Piemonte
Country [76] 0 0
Italy
State/province [76] 0 0
Toscana
Country [77] 0 0
Italy
State/province [77] 0 0
Trentino-Sudtirol
Country [78] 0 0
Italy
State/province [78] 0 0
Arezzo
Country [79] 0 0
Italy
State/province [79] 0 0
Bari
Country [80] 0 0
Italy
State/province [80] 0 0
Genova
Country [81] 0 0
Italy
State/province [81] 0 0
Palermo
Country [82] 0 0
Italy
State/province [82] 0 0
Roma
Country [83] 0 0
Italy
State/province [83] 0 0
Verona
Country [84] 0 0
Japan
State/province [84] 0 0
Aomori
Country [85] 0 0
Japan
State/province [85] 0 0
Ehime
Country [86] 0 0
Japan
State/province [86] 0 0
Ibaraki
Country [87] 0 0
Japan
State/province [87] 0 0
Kanagawa
Country [88] 0 0
Japan
State/province [88] 0 0
Nara
Country [89] 0 0
Japan
State/province [89] 0 0
Shizuoka
Country [90] 0 0
Japan
State/province [90] 0 0
Chiba
Country [91] 0 0
Japan
State/province [91] 0 0
Fukuoka
Country [92] 0 0
Japan
State/province [92] 0 0
Osaka
Country [93] 0 0
Japan
State/province [93] 0 0
Tokyo
Country [94] 0 0
Korea, Republic of
State/province [94] 0 0
Seoul
Country [95] 0 0
Malaysia
State/province [95] 0 0
Kuala Lumpur
Country [96] 0 0
Netherlands
State/province [96] 0 0
Limburg
Country [97] 0 0
Netherlands
State/province [97] 0 0
Zuid-Holland
Country [98] 0 0
Netherlands
State/province [98] 0 0
Utrecht
Country [99] 0 0
Norway
State/province [99] 0 0
Akershus
Country [100] 0 0
Norway
State/province [100] 0 0
Rogaland
Country [101] 0 0
Peru
State/province [101] 0 0
Lima
Country [102] 0 0
Peru
State/province [102] 0 0
Muni Metro De Lima
Country [103] 0 0
Poland
State/province [103] 0 0
Dolnoslaskie
Country [104] 0 0
Poland
State/province [104] 0 0
Kujawsko-pomorskie
Country [105] 0 0
Poland
State/province [105] 0 0
Malopolskie
Country [106] 0 0
Poland
State/province [106] 0 0
Mazowieckie
Country [107] 0 0
Poland
State/province [107] 0 0
Podkarpackie
Country [108] 0 0
Poland
State/province [108] 0 0
Pomorskie
Country [109] 0 0
Poland
State/province [109] 0 0
Slaskie
Country [110] 0 0
Poland
State/province [110] 0 0
Wielkopolskie
Country [111] 0 0
Portugal
State/province [111] 0 0
Lisboa
Country [112] 0 0
Portugal
State/province [112] 0 0
Braga
Country [113] 0 0
Portugal
State/province [113] 0 0
Coimbra
Country [114] 0 0
Portugal
State/province [114] 0 0
Porto
Country [115] 0 0
Puerto Rico
State/province [115] 0 0
Ponce
Country [116] 0 0
Spain
State/province [116] 0 0
La Coruna
Country [117] 0 0
Spain
State/province [117] 0 0
Madrid, Comunidad De
Country [118] 0 0
Spain
State/province [118] 0 0
Navarra
Country [119] 0 0
Spain
State/province [119] 0 0
Barcelona
Country [120] 0 0
Spain
State/province [120] 0 0
Madrid
Country [121] 0 0
Spain
State/province [121] 0 0
Valencia
Country [122] 0 0
Switzerland
State/province [122] 0 0
Basel-Stadt
Country [123] 0 0
Switzerland
State/province [123] 0 0
Geneve
Country [124] 0 0
Switzerland
State/province [124] 0 0
Zurich
Country [125] 0 0
Taiwan
State/province [125] 0 0
Taichung
Country [126] 0 0
Taiwan
State/province [126] 0 0
Taipei
Country [127] 0 0
Turkey
State/province [127] 0 0
Ankara
Country [128] 0 0
Turkey
State/province [128] 0 0
Eskisehir
Country [129] 0 0
Turkey
State/province [129] 0 0
Istanbul
Country [130] 0 0
Turkey
State/province [130] 0 0
Izmir
Country [131] 0 0
Turkey
State/province [131] 0 0
Konya
Country [132] 0 0
United Kingdom
State/province [132] 0 0
Highland
Country [133] 0 0
United Kingdom
State/province [133] 0 0
London, City Of

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: http://engagezone.msd.com/ds_documentation.php


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.