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)

Phase 3Active Not RecruitingNCT03711032

Merck Sharp & Dohme LLC1,397 enrolled

Overview

Researchers are looking for new ways to treat high-risk non muscle invasive bladder cancer (HR NMIBC). NMIBC is cancer in the tissue that lines the inside of the bladder but has not spread to the bladder muscle or outside of the bladder. High-risk means NMIBC may have a high chance of getting worse or coming back after treatment. The goals of this study are to learn: 1. If more people who receive pembrolizumab with Bacillus Calmette-Guerin (BCG) have no signs of cancer in their body and live longer without the cancer growing, spreading, or coming back compared to people who receive BCG alone. 2. About the safety and how well people tolerate BCG alone or in combination with pembrolizumab.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,397

Conditions

High-risk Non-muscle Invasive Bladder Cancer

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 Naïve Cohort (Cohort B) Only \- Has received any prior treatment with BCG for their NMIBC within the past 2 years prior to study entry

Locations (206)

Alaska Urological Institute dba Alaska Clinical Research Center ( Site 1083)

Anchorage, Alaska, United States

Mayo Clinic in Arizona - Phoenix ( Site 1094)

Phoenix, Arizona, United States

Arizona Urology Specialists (AUS)-Professional Park ( Site 1096)

Tucson, Arizona, United States

UCLA Hematology/Oncology - Westwood (Building 200 Suite 140)-Department of Urology/Institute of Uro

Los Angeles, California, United States

University of California Irvine Medical Center ( Site 1061)

Orange, California, United States

Outcomes

Primary Outcomes

Complete Response Rate (CRR) by Blinded Independent Central Review (BICR) (Cohort A)

CRR is defined as the percentage of participants with carcinoma in situ (CIS) achieving a complete response (CR).

Time frame: Up to ~3.5 years

Event-Free Survival (EFS) (Cohort B)

EFS is defined as the time from randomization until urothelial carcinoma (UC)-defined event, or death due to any cause.

Time frame: Up to ~5 years

Secondary Outcomes

EFS (Cohort A)

EFS is defined as the time from randomization until UC-defined event, or death due to any cause.

Time frame: Up to ~5 years

Recurrence-Free Survival (RFS) (Cohorts A and B)

RFS is defined as the time from randomization until the first occurrence of any UC recurrence, progression, or death due to any cause.

Time frame: Up to ~5 years

Overall Survival (OS) (Cohorts A and B)

OS is defined as the time from randomization to death due to any cause.

Time frame: Up to ~5 years

Disease Specific Survival (DSS) (Cohorts A and B)

DSS is defined as the time from randomization to death due to bladder cancer.

Time frame: Up to ~5 years

Time to Cystectomy (Cohorts A and B)

Time to cystectomy is defined as the time from a participant's randomization until the date of cystectomy.

Time frame: Up to ~5 years

12-Month EFS Rate (Cohort A)

EFS is defined as the time from randomization until UC-defined event, or death due to any cause. The 12-month EFS rate is defined as the percentage of participants with EFS at 12 months.

Time frame: 12 months after EFS (up to ~5 years)

Duration of Response (DOR) (Cohorts A and B)

DOR in participants with CIS is defined as the time from first documented CR until end of response or death due to any cause, whichever occurs first.

Time frame: Up to ~5 years

12-Month DOR Rate (Cohorts A and B)

The 12-month DOR Rate in participants with CIS is defined as the percentage of participants with a CR of at least 12 months duration.

Time frame: 12 months after CR (up to ~4.5 years)

Percentage of Participants Experiencing Adverse Events (AEs) (Cohorts A and B)

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.

Time frame: Up to ~5 years

Percentage of Participants Discontinuing Study Drug Due to AEs (Cohorts A and B)

Time frame: Up to ~5 years

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)

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.

Time frame: Baseline, time of last PRO assessment (up to ~2 years)

Change from Baseline in EORTC-QLQ-C30 Physical Functioning (Items 1-5) Combined Score (Cohorts A and B)

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.

Time frame: Baseline, time of last PRO assessment (up to ~2 years)

Change from Baseline in EORTC-QLQ-Non-muscle Invasive Bladder Cancer Module 24 (NMIBC24) Total Score (Cohorts A and B)

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.

Time frame: Baseline, time of last PRO assessment (up to ~2 years)

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)

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.

Time frame: Baseline, time of last PRO assessment (up to ~2 years)

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)

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.

Time frame: Time of last PRO assessment (up to ~2 years)

TTD in the EQ-5D-5L VAS (Cohorts A and B)

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.

Time frame: Time of last PRO assessment (up to ~2 years)

CRR by BICR (Cohort B)

CRR is defined as the percentage of participants with CIS achieving a CR.

Time frame: Up to ~3.5 years

24-Month EFS Rate (Cohort B)

EFS is defined as the time from randomization until UC-defined event, or death due to any cause. The 24-month EFS rate is defined as the percentage of participants with EFS at 24 months.

Time frame: 24 months after EFS (Up to ~5 years)