Clinical Trials /

Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Muscle-invasive Bladder Cancer (MIBC) (MK-3475-992/KEYNOTE-992)

NCT04241185

Description:

This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with chemoradiotherapy (CRT) versus CRT alone in participants with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that pembrolizumab + chemoradiotherapy is superior to placebo + chemoradiotherapy with respect to bladder intact event-free survival.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Muscle-invasive Bladder Cancer (MIBC) (MK-3475-992/KEYNOTE-992)
  • Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Participants With Muscle-invasive Bladder Cancer (MIBC) (KEYNOTE-992)

Clinical Trial IDs

  • ORG STUDY ID: 3475-992
  • SECONDARY ID: MK-3475-992
  • SECONDARY ID: 2019-004023-20
  • NCT ID: NCT04241185

Conditions

  • Urinary Bladder Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Pembrolizumab + Chemotherapy + Radiotherapy
CisplatinPembrolizumab + Chemotherapy + Radiotherapy
Fluorouracil (5-FU)Pembrolizumab + Chemotherapy + Radiotherapy
Mitomycin C (MMC)Pembrolizumab + Chemotherapy + Radiotherapy
GemcitabinePembrolizumab + Chemotherapy + Radiotherapy
Placebo to PembrolizumabPlacebo + Chemotherapy + Radiotherapy

Purpose

This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with chemoradiotherapy (CRT) versus CRT alone in participants with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that pembrolizumab + chemoradiotherapy is superior to placebo + chemoradiotherapy with respect to bladder intact event-free survival.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + Chemotherapy + RadiotherapyExperimentalParticipants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.
  • Pembrolizumab
  • Cisplatin
  • Fluorouracil (5-FU)
  • Mitomycin C (MMC)
  • Gemcitabine
Placebo + Chemotherapy + RadiotherapyPlacebo ComparatorParticipants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.
  • Cisplatin
  • Fluorouracil (5-FU)
  • Mitomycin C (MMC)
  • Gemcitabine
  • Placebo to Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Has a histologically confirmed diagnosis of MIBC with predominant urothelial histology

          -  Has clinically non-metastatic bladder cancer (N0M0)

          -  Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the
             protocol-specified radiosensitizing chemotherapy regimens

          -  Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          -  Demonstrates adequate organ function

          -  Male participants are eligible to participate if they agree to the following during
             the intervention period and for at least 180 days after the last dose of study
             intervention:

               -  Refrain from donating sperm

               -  Be abstinent from heterosexual intercourse as their preferred and usual lifestyle
                  (abstinent on a long term and persistent basis) and agree to remain abstinent; or
                  must agree to use contraception unless confirmed to be azoospermic

          -  A female participant is eligible to participate if she is not pregnant or
             breastfeeding, and at least one of the following conditions applies:

               -  Is not a woman of childbearing potential (WOCBP)

               -  Is a WOCBP and using a contraceptive method that is highly effective (with a
                  failure rate of <1% per year), with low user dependency or be abstinent from
                  heterosexual intercourse as their preferred and usual lifestyle (abstinent on a
                  long term and persistent basis), during the intervention period and for at least
                  180 days after the last dose of study intervention; and agrees not to donate eggs
                  (ova, oocytes) to others or freeze/store for her own use for the purpose of
                  reproduction during this period

        Exclusion Criteria:

          -  Has the presence of diffuse carcinoma in situ (CIS) (multiple foci of CIS) throughout
             the bladder

          -  Has the presence of urothelial carcinoma (UC) at any site outside of the urinary
             bladder in the previous 2 years except for Ta stage/T1 stage/CIS of the upper tract if
             the participant has undergone a complete nephroureterectomy

          -  Has a known additional malignancy that is progressing or has required active therapy
             within the past 3 years, except basal cell carcinoma of the skin, squamous cell
             carcinoma of the skin, superficial bladder cancer or other carcinoma in situ that has
             undergone potentially curative therapy

          -  Has the presence of bilateral hydronephrosis

          -  Has limited bladder function with frequency of small amounts of urine (< 30 mL),
             urinary incontinence, or requires self-catheterization or a permanent indwelling
             catheter

          -  Has received prior pelvic/local radiation therapy or any antineoplastic treatment for
             muscle-invasive bladder cancer (MIBC). Treatment for non-muscle invasive bladder
             cancer (NMIBC) with intravesical instillation therapy that was completed ≥28 days
             prior to randomization is allowed. Prior systemic treatment of NMIBC is not permitted.

          -  Received prior therapy with an anti-PD-1 (programmed cell death protein 1), anti-PD-L1
             (programmed death-ligand 1), or anti-PD-L2 (programmed cell death 1 ligand 2), or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
             CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], OX 40, or CD137 [cluster of
             differentiation 137])

          -  Has received a live vaccine within 30 days prior to the first dose of study drug

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study intervention

          -  Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or the selected
             chemotherapy regimen, and/or any of their excipients

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug

          -  Has an active autoimmune disease that has required systemic treatment in the past 2
             years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency) is not considered a form
             of systemic treatment and is allowed

          -  Has a history of non-infectious pneumonitis that required steroids or has current
             pneumonitis

          -  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 a known history of active tuberculosis (TB; Bacillus tuberculosis)

          -  Has a known psychiatric or substance abuse disorder that would interfere with the
             participant's ability to cooperate with the requirements of the study

          -  Has had an allogenic tissue/solid organ transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Bladder Intact Event-Free Survival (BI-EFS)
Time Frame:Up to approximately 71 months
Safety Issue:
Description:BI-EFS is defined as the time from randomization to any of the following events: residual/recurrent MIBC post-chemoradiotherapy (CRT), nodal or distant metastases post-CRT, radical cystectomy, or death due to any cause. The BI-EFS for all participants will be presented.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to approximately 83 months
Safety Issue:
Description:Time from randomization to death due to any cause.
Measure:Metastasis-Free Survival (MFS)
Time Frame:Up to approximately 83 months
Safety Issue:
Description:MFS is defined as the time from randomization to the first documented occurrence of nodal or distant metastases as assessed by computerized tomography (CT) or magnetic resonance imaging (MRI) per blinded independent central review (BICR) and/or biopsy results assessed by central pathology review. If biopsy is not feasible due to participant safety, CT/MRI alone will be sufficient.
Measure:Time to Cystectomy
Time Frame:Up to approximately 83 months
Safety Issue:
Description:Time to cystectomy is defined as time from a participant's randomization to date of cystectomy.
Measure:Time to Occurrence of Non-Muscle-Invasive Bladder Cancer (NMIBC)
Time Frame:Up to approximately 83 months
Safety Issue:
Description:Time to occurrence of low-grade disease, defined as the time from randomization until the development of NMIBC, will be presented.
Measure:Number of Participants Who Experienced One or More Adverse Events (AEs)
Time Frame:Up to approximately 83 months
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented.
Measure:Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE)
Time Frame:Up to approximately 1 year
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented.
Measure:Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
Time Frame:Baseline and up to approximately 83 months
Safety Issue:
Description: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). 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.
Measure:Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
Time Frame:Baseline and up to approximately 83 months
Safety Issue:
Description: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). 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.
Measure:Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
Time Frame:Baseline and up to approximately 83 months
Safety Issue:
Description:The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. The change from baseline in the combined scores of the urinary, bowel, and sexual domains of the BCI will be presented.
Measure:Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L)
Time Frame:Baseline and up to approximately 83 months
Safety Issue:
Description: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.
Measure:Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
Time Frame:Up to approximately 83 months
Safety Issue:
Description: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). 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.
Measure:Time to Deterioration (TTD) in Physical Functioning (Items 1-5) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
Time Frame:Up to approximately 83 months
Safety Issue:
Description: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). A higher score indicates a better quality of life. TTD in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score is defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores.
Measure:Time to Deterioration (TTD) in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
Time Frame:Up to approximately 83 months
Safety Issue:
Description:The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. TTD in BCI is defined as a 6, 7, and 7 points or greater worsening from baseline for urinary, bowel, and sexual domains, respectively, with or without subsequent confirmation, under a right-censoring rule.
Measure:Time to Deterioration (TTD) in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L)
Time Frame:Up to approximately 83 months
Safety Issue:
Description: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". 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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Last Updated

June 5, 2020