A Phase 3 Study of BCG with or without Pembrolizumab for the Treatment of Non-Muscle-Invasive High-Risk Bladder Cancer (MK-3475-676)
Summary description of the study
The immune system plays an important role in tumor control. Pembrolizumab is an antibody that can prevent the inhibition of the immune system by the tumor and thus enhance the body's natural fight against it. The study investigates the efficacy and tolerability of Pembrolizumab and BCG compared to standard therapy with BCG alone. Study participants will receive the investigational drug or drugs for approximately 2-3 years, provided no safety concerns arise and their cancer does not worsen.
(BASEC)
Intervention under investigation
Approximately 550 patients are expected to participate in this study worldwide. In Switzerland, 15 patients are planned. After careful eligibility assessment, medical history collection, and detailed information, the participant will be enrolled in the study and randomly assigned to one of the two treatment arms (treatment with Pembrolizumab & BCG or treatment with BCG alone). Each participant will receive BCG. The probability of receiving Pembrolizumab in addition is 50%. Both study participants and the study physician are aware of the applied therapy. All participants will receive BCG via bladder instillation once a week for the first 6 weeks at the start of the study, as well as once weekly over a period of three weeks after 3, 5, 12, 18, 24, 30, and 36 months. During the first two years, participants in the combination therapy will additionally receive Pembrolizumab intravenously every three weeks (35 cycles). Subsequently, study participants will enter the follow-up phase. If the cancer worsens during the study or if the therapy needs to be changed, the participant will be contacted approximately every 12 weeks or more frequently and their health status will be checked. As part of the study visits, various measures and examinations may occur, such as: discussion of well-being and current medication, intravenous therapy, imaging procedures such as a CTU (computed tomography urography), cystoscopy (if necessary with tissue sampling or surgical removal of a bladder tumor), electrocardiogram (ECG), samples of blood, urine, or tissue, questionnaires as well as examination of vital signs.
(BASEC)
Disease under investigation
This study will include patients aged 18 years and older with persistent or recurrent non-muscle-invasive high-risk bladder cancer after prior induction therapy with BCG (Bacillus Calmette Guérin, an attenuated bacterium). Although bladder instillation with BCG is routinely used for bladder cancer and can achieve a cure, the disease recurs in many patients after such treatment or even spreads to the deeper muscle layer. This study investigates a therapy aimed at reducing the risk of disease progression or recurrence and thus increasing the likelihood of bladder preservation.
(BASEC)
• Confirmed non-muscle-invasive high-risk bladder cancer (HR NMIBC) (tissue type predominantly urothelial carcinoma) • There must have been prior treatment of the disease with BCG (induction therapy, at least 5 bladder instillations within a period of 10 weeks), but no further treatment series (additional induction or maintenance therapy) • Persistent or recurrent HR NMIBC after the above-mentioned treatment (induction therapy) (BASEC)
Exclusion criteria
• Persistent disease of classification T1 after BCG induction therapy • Muscle-invasive, locally advanced, unresectable or metastatic bladder cancer • Concurrent non-muscle-invasive urothelial carcinoma occurring outside the bladder, concurrent occurrence of the disease in the upper urinary tract, or concurrent invasive prostate cancer (BASEC)
Trial sites
Basel, Geneva, Zurich
(BASEC)
Sponsor
MSD Merck Sharp & Dohme AG, Switzerland Merck Sharp & Dohme LLC, USA
(BASEC)
Contact
Contact Person Switzerland
Klaudia Georgi
+41 58 618 33 88
klaudia.georgi@cluttermsd.comMSD Merck Sharp & Dohme AG
(BASEC)
General Information
Merck Sharp & Dohme LLC
(ICTRP)
Scientific Information
Merck Sharp & Dohme LLC
(ICTRP)
Name of the authorising ethics committee (for multicentre studies, only the lead committee)
Ethics Committee Zurich
(BASEC)
Date of authorisation
05.03.2019
(BASEC)
ICTRP Trial ID
NCT03711032 (ICTRP)
Official title (approved by ethics committee)
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) (BASEC)
Academic 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 Nave to BCG Treatment (KEYNOTE-676) (ICTRP)
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) (ICTRP)
Disease under investigation
High-risk Non-muscle Invasive Bladder Cancer (ICTRP)
Intervention under investigation
Biological: PembrolizumabBiological: BCG (ICTRP)
Type of trial
Interventional (ICTRP)
Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)
Inclusion/Exclusion criteria
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 Nave Cohort (Cohort B) Only
- Has received any prior treatment with BCG for their NMIBC within the past 2 years prior
to study entry (ICTRP)
not available
Primary and secondary end points
Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) (Cohort A);Event-Free Survival (EFS) (Cohort B) (ICTRP)
EFS (Cohort A);Recurrence-Free Survival (RFS) (Cohorts A and B);Overall Survival (OS) (Cohorts A and B);Disease Specific Survival (DSS) (Cohorts A and B);Time to Cystectomy (Cohorts A and B);12-Month EFS Rate (Cohort A);Duration of Response (DOR) (Cohorts A and B);12-Month DOR Rate (Cohorts A and B);Percentage of Participants Experiencing Adverse Events (AEs) (Cohorts A and B);Percentage of Participants Discontinuing Study Drug Due to AEs (Cohorts A and B);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);Change from Baseline in EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score (Cohorts A and B);Change from Baseline in EORTC-QLQ-Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score (Cohorts A and B);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 to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Cohorts A and B);TTD in the EQ-5D-5L VAS (Cohorts A and B);CRR by BICR (Cohort B);24-Month EFS Rate (Cohort B) (ICTRP)
Registration date
15.10.2018 (ICTRP)
Incorporation of the first participant
not available
Secondary sponsors
not available
Additional contacts
Medical Director, Merck Sharp & Dohme LLC (ICTRP)
Secondary trial IDs
MK-3475-676, 194713, jRCT2031200390, 2022-501817-29-00, U1111-1282-1555, 2018-001967-22, 3475-676 (ICTRP)
Results-Individual Participant Data (IPD)
not available
Further information on the trial
https://clinicaltrials.gov/study/NCT03711032 (ICTRP)
Results of the trial
Results summary
not available
Link to the results in the primary register
not available