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/show/NCT03711032




Registration number
NCT03711032
Ethics application status
Date submitted
15/10/2018
Date registered
18/10/2018
Date last updated
25/07/2019

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 Persistent or Recurrent Following BCG Induction (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

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

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).

Experimental: BCG (Arm 2) - Participants receive BCG monotherapy (Induction and Maintenance).


Other interventions: Pembrolizumab
Pembrolizumab IV infusion of 200 mg Q3W

Other interventions: BCG
BCG (intravesical instillation): 50 mg (wet weight) of powder for instillation fluid for intravesical use, administered during Induction and Maintenance therapy

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

Outcomes
Primary outcome [1] 0 0
Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) - CRR is defined as the percentage of participants with CIS achieving a complete response (CR).
Timepoint [1] 0 0
Up to ~3.5 years
Secondary outcome [1] 0 0
Event-Free Survival (EFS) - EFS is defined as the time from randomization until the reccurrence or progression of HR NMIBC, or death due to any cause.
Timepoint [1] 0 0
Up to ~5 years
Secondary outcome [2] 0 0
Recurrence-Free Survival (RFS) - RFS is defined as the time from randomization until the first occurrence of any urothelial carcinoma (UC) recurrence, or death due to any cause.
Timepoint [2] 0 0
Up to ~5 years
Secondary outcome [3] 0 0
Overall Survival (OS) - OS is defined as the time from randomization to death due to any cause.
Timepoint [3] 0 0
Up to ~5 years
Secondary outcome [4] 0 0
Disease Specific Survival (DSS) - DSS is defined as the time from randomization to death due to bladder cancer.
Timepoint [4] 0 0
Up to ~5 years
Secondary outcome [5] 0 0
Time to Cystectomy - Time to cystectomy is defined as the time from a participant's randomization until the date of cystectomy.
Timepoint [5] 0 0
Up to ~5 years
Secondary outcome [6] 0 0
12-Month EFS Rate - The 12-month EFS rate is defined as the probability of maintaining EFS at 12 months.
Timepoint [6] 0 0
12 months after EFS (up to ~5 years)
Secondary outcome [7] 0 0
Duration of Response (DOR) - DOR is defined as the time from first documented evidence of CR until disease progression or death due to any cause, whichever occurs first.
Timepoint [7] 0 0
Up to ~5 years
Secondary outcome [8] 0 0
12-Month DOR Rate - The 12-month DOR Rate is defined as probability of maintaining DOR at 12 months.
Timepoint [8] 0 0
12 months after CR (up to ~4.5 years)
Secondary outcome [9] 0 0
Time to True Deterioration (TTD) in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ-C30) - 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.
Timepoint [9] 0 0
time of last PRO assessment (up to ~2 years)
Secondary outcome [10] 0 0
Percentage of Participants Experiencing Adverse Events (AEs) - 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.
Timepoint [10] 0 0
Up to ~5 years
Secondary outcome [11] 0 0
Percentage of Participants Discontinuing Study Drug Due to AEs - 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.
Timepoint [11] 0 0
Up to ~5 years
Secondary outcome [12] 0 0
Change From Baseline in EORTC-QLQ-C30 Global Health Status (Item 29) Scale Score - 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.
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-C30 Quality of Life (Item 30) Scale Score - 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.
Timepoint [13] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [14] 0 0
Change from Baseline in EORTC-QLQ-C30 Score - 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.
Timepoint [14] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [15] 0 0
Change from Baseline in EORTC QLQ-Non-Muscle Invasive Bladder Cancer Module 24 (NMIBC24) Score - 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.
Timepoint [15] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [16] 0 0
Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Index Score - 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".
Timepoint [16] 0 0
Baseline, time of last PRO assessment (up to ~2 years)
Secondary outcome [17] 0 0
Change from Baseline in EuroQoL Visual Analogue Score (EQ VAS) - 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".
Timepoint [17] 0 0
Baseline, time of last PRO assessment (up to ~2 years)

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

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, (Australia)NSW
Recruitment hospital [1] 0 0
Sydney Adventist Hospital ( Site 0001) - Wahroonga
Recruitment hospital [2] 0 0
Nothern Cancer Institute ( Site 0003) - St Leonards
Recruitment postcode(s) [1] 0 0
2076 - Wahroonga
Recruitment postcode(s) [2] 0 0
2065 - St Leonards
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
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Kansas
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
New Jersey
Country [8] 0 0
United States of America
State/province [8] 0 0
New York
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
South Carolina
Country [12] 0 0
United States of America
State/province [12] 0 0
Tennessee
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas
Country [14] 0 0
United States of America
State/province [14] 0 0
Vermont
Country [15] 0 0
United States of America
State/province [15] 0 0
Virginia
Country [16] 0 0
Austria
State/province [16] 0 0
Innsbruck
Country [17] 0 0
Austria
State/province [17] 0 0
Linz
Country [18] 0 0
Belgium
State/province [18] 0 0
Aalst
Country [19] 0 0
Belgium
State/province [19] 0 0
Gent
Country [20] 0 0
Belgium
State/province [20] 0 0
Yvoir
Country [21] 0 0
Canada
State/province [21] 0 0
British Columbia
Country [22] 0 0
Canada
State/province [22] 0 0
New Brunswick
Country [23] 0 0
Canada
State/province [23] 0 0
Ontario
Country [24] 0 0
Canada
State/province [24] 0 0
Quebec
Country [25] 0 0
Finland
State/province [25] 0 0
Tampere
Country [26] 0 0
Germany
State/province [26] 0 0
Jena
Country [27] 0 0
Germany
State/province [27] 0 0
Munich
Country [28] 0 0
Germany
State/province [28] 0 0
Trier
Country [29] 0 0
Germany
State/province [29] 0 0
Weiden In Der Oberpfalz
Country [30] 0 0
Greece
State/province [30] 0 0
Larissa
Country [31] 0 0
Greece
State/province [31] 0 0
Thessaloniki
Country [32] 0 0
Italy
State/province [32] 0 0
GE
Country [33] 0 0
Italy
State/province [33] 0 0
Bari
Country [34] 0 0
Italy
State/province [34] 0 0
Bolzano
Country [35] 0 0
Italy
State/province [35] 0 0
Firenze
Country [36] 0 0
Italy
State/province [36] 0 0
Milan
Country [37] 0 0
Italy
State/province [37] 0 0
Palermo
Country [38] 0 0
Italy
State/province [38] 0 0
Roma
Country [39] 0 0
Italy
State/province [39] 0 0
Verona
Country [40] 0 0
Japan
State/province [40] 0 0
Ehime
Country [41] 0 0
Japan
State/province [41] 0 0
Kanagawa
Country [42] 0 0
Japan
State/province [42] 0 0
Nara
Country [43] 0 0
Japan
State/province [43] 0 0
Chiba
Country [44] 0 0
Japan
State/province [44] 0 0
Fukuoka
Country [45] 0 0
Japan
State/province [45] 0 0
Osaka
Country [46] 0 0
Japan
State/province [46] 0 0
Tokyo
Country [47] 0 0
Korea, Republic of
State/province [47] 0 0
Seoul
Country [48] 0 0
Malaysia
State/province [48] 0 0
Kuala Lumpur
Country [49] 0 0
Netherlands
State/province [49] 0 0
Rotterdam
Country [50] 0 0
Norway
State/province [50] 0 0
Lorenskog
Country [51] 0 0
Norway
State/province [51] 0 0
Stavanger
Country [52] 0 0
Peru
State/province [52] 0 0
Lima
Country [53] 0 0
Poland
State/province [53] 0 0
Koscierzyna
Country [54] 0 0
Poland
State/province [54] 0 0
Rybnik
Country [55] 0 0
Poland
State/province [55] 0 0
Siedlce
Country [56] 0 0
Poland
State/province [56] 0 0
Slupsk
Country [57] 0 0
Poland
State/province [57] 0 0
Warszawa
Country [58] 0 0
Poland
State/province [58] 0 0
Wroclaw
Country [59] 0 0
Portugal
State/province [59] 0 0
Braga
Country [60] 0 0
Portugal
State/province [60] 0 0
Coimbra
Country [61] 0 0
Portugal
State/province [61] 0 0
Lisboa
Country [62] 0 0
Portugal
State/province [62] 0 0
Porto
Country [63] 0 0
Spain
State/province [63] 0 0
Madrid
Country [64] 0 0
Spain
State/province [64] 0 0
Navarra
Country [65] 0 0
Spain
State/province [65] 0 0
Lugo
Country [66] 0 0
Spain
State/province [66] 0 0
Valencia
Country [67] 0 0
Switzerland
State/province [67] 0 0
Basel
Country [68] 0 0
Switzerland
State/province [68] 0 0
Geneve
Country [69] 0 0
Switzerland
State/province [69] 0 0
Zurich
Country [70] 0 0
Turkey
State/province [70] 0 0
Eskisehir
Country [71] 0 0
Turkey
State/province [71] 0 0
Izmir
Country [72] 0 0
Turkey
State/province [72] 0 0
Konya
Country [73] 0 0
United Kingdom
State/province [73] 0 0
Highland
Country [74] 0 0
United Kingdom
State/province [74] 0 0
Tooting
Country [75] 0 0
United Kingdom
State/province [75] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT03711032
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
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
Trialsites@merck.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03711032