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Safety and Efficacy Study of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (MK-3475-564/KEYNOTE-564)

NCT03142334

Description:

The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) in the adjuvant treatment of adult participants who have undergone nephrectomy and have intermediate-high risk, high risk, or M1 no evidence of disease (M1 NED) renal cell carcinoma (RCC) with clear cell component. The primary study hypothesis is that pembrolizumab is superior to placebo with respect to Disease-free Survival (DFS) as assessed by the Investigator in male and female participants with intermediate-high risk, high risk and M1 NED RCC.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy Study of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (MK-3475-564/KEYNOTE-564)
  • Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)

Clinical Trial IDs

  • ORG STUDY ID: 3475-564
  • SECONDARY ID: 2016-004351-75
  • SECONDARY ID: 173704
  • SECONDARY ID: MK-3475-564
  • NCT ID: NCT03142334

Conditions

  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabMK-3475Pembrolizumab
Placebo (saline solution)saline solutionPlacebo

Purpose

The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) in the adjuvant treatment of adult participants who have undergone nephrectomy and have intermediate-high risk, high risk, or M1 no evidence of disease (M1 NED) renal cell carcinoma (RCC) with clear cell component. The primary study hypothesis is that pembrolizumab is superior to placebo with respect to Disease-free Survival (DFS) as assessed by the Investigator in male and female participants with intermediate-high risk, high risk and M1 NED RCC.

Detailed Description

      Participants will be assigned to receive study treatment until disease recurrence,
      unacceptable adverse events (AEs), intercurrent illness that prevents further administration
      of treatment, Investigator's decision to withdraw the participant, noncompliance with study
      treatment or procedural requirements, administrative reasons requiring cessation of
      treatment, or until the participant has received 17 cycles of study treatment (approximately
      1 year). Each cycle is 3 weeks long.
    

Trial Arms

NameTypeDescriptionInterventions
PembrolizumabExperimentalParticipants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 17 cycles.
  • Pembrolizumab
PlaceboPlacebo ComparatorParticipants receive placebo (saline solution) via IV infusion on Day 1 of each 3-week cycle for up to 17 cycles.
  • Placebo (saline solution)

Eligibility Criteria

        Inclusion Criteria:

          -  Has histologically confirmed diagnosis of RCC with clear cell component with or
             without sarcomatoid features.

          -  Female participants of childbearing potential must be willing to use an adequate
             method of contraception, for the course of the study through 120 days after the last
             dose of study treatment.

          -  Male participants of childbearing potential must agree to use an adequate method of
             contraception, starting with the first dose of study treatment through 120 days after
             the last dose of study treatment.

          -  Has intermediate-high risk, high risk, or M1 NED RCC as defined by the following
             pathological tumor-node-metastasis and Fuhrman grading status:

               1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, Any Grade,
                  N0, M0

               2. High risk RCC: pT4, Any Grade N0, M0; pT, Any stage, Any Grade, N+, M0

               3. M1 NED RCC participants who present not only with the primary kidney tumor but
                  also solid, isolated, soft tissue metastases that can be completely resected at
                  one of the following: the time of nephrectomy (synchronous) or, ≤1 year from
                  nephrectomy (metachronous).

          -  Has received no prior systemic therapy for advanced RCC.

          -  Has undergone a partial nephroprotective or radical complete nephrectomy (and complete
             resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants)
             with negative surgical margins.

          -  Must have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing
             informed consent and ≤12 weeks prior to randomization.

          -  Must be tumor-free as assessed by the Investigator and validated by either computed
             tomography (CT) or magnetic resonance imaging (MRI) scan of the brain and chest,
             abdomen, and pelvis and a bone scan ≤28 days from randomization.

          -  Must have provided adequate tissue per the following: Nephrectomy only: tissue from
             nephrectomy (required); Synchronous M1 NED: tissue from nephrectomy (required) AND,
             metastasectomy tissue (if available); Metachronous M1 NED: tissue from metastasectomy
             (required) AND, nephrectomy tissue (if available).

          -  Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or
             1.

          -  Has adequate organ function.

        Exclusion Criteria:

          -  Has had major surgery, other than nephrectomy and/or resection of pre-existing
             metastases for M1 NED participants, within 12 weeks prior to randomization.

          -  Has received prior radiotherapy for RCC.

          -  Has pre-existing brain or bone metastatic lesions.

          -  Has residual thrombus post nephrectomy in the vena renalis or vena cava.

          -  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 the first dose of study treatment.

          -  Has an active autoimmune disease that has required systemic treatment in past 2 years
             (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive
             drugs). Replacement therapy is allowed.

          -  Has a known additional malignancy that is progressing or required active treatment ≤3
             years ago. Exceptions include early-stage cancers (carcinoma in situ or Stage 1)
             treated with curative intent, basal cell carcinoma of the skin, squamous cell
             carcinoma of the skin, in situ cervical cancer, in situ prostate cancer, or in situ
             breast cancer that has undergone potentially curative therapy.

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

          -  Has an active infection requiring systemic therapy.

          -  Has a history of, or is currently on, dialysis.

          -  Has a known history of human immunodeficiency virus (HIV) infection.

          -  Has known active hepatitis B or hepatitis C virus infection.

          -  Has a known history of active tuberculosis (Bacillus tuberculosis).

          -  Has had a prior solid organ transplant.

          -  Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the Screening visit through 120 days
             after the last dose of study treatment.

          -  Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),
             anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent
             directed to another co-inhibitory T-cell receptor (i.e., cytotoxic
             T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137 [tumor necrosis factor
             receptor superfamily member 9 (TNFRSF9)]) or has previously participated in a Merck
             pembrolizumab (MK-3475) clinical trial.

          -  Has received prior anticancer therapy, monoclonal antibody, chemotherapy, or an
             investigational agent or device within 4 weeks or 5 half-lives (whichever is longer)
             before first dose of study treatment or not recovered (i.e., must be ≤ Grade 1 or at
             Baseline) from AEs due to previously administered agents.

          -  Has received a live vaccine within 30 days prior to the first dose 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 prior to the first dose of
             study treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease-free Survival (DFS) as Assessed by the Investigator
Time Frame:Up to approximately 72 months
Safety Issue:
Description:DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, distant metastasis, secondary systemic malignancy, or death due to any cause, whichever occurs first.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to approximately 72 months
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Adverse Events (AEs)
Time Frame:Nonserious AEs: Up to 30 days after last dose of study treatment (Up to approximately 13 months); Serious AEs: Up to 90 days after last dose of study treatment (Up to approximately 15 months)
Safety Issue:
Description:An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Participants are monitored for the occurrence of nonserious AEs for up to 30 days after last dose of study treatment and of serious AEs for up to 90 days after last dose of study treatment. The number of participants who experience an AE will be assessed.
Measure:Study Treatment Discontinuations Due to an AE
Time Frame:Up to approximately 12 months
Safety Issue:
Description:An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who discontinue study treatment due to an AE will be assessed.
Measure:First Local Disease Recurrence-specific Survival (DRSS1) as Assessed by the Investigator
Time Frame:Up to approximately 72 months
Safety Issue:
Description:DRSS1 is defined as the time from randomization to the first documented local recurrence of RCC as assessed by the investigator. For DRSS1, only local recurrence is counted as an event.
Measure:First Local Recurrence with Visceral Lesion or Distant Metastasis with Visceral Lesion or Secondary Systemic Malignancy with Visceral Lesion (DRSS2) as Assessed by the Investigator
Time Frame:Up to approximately 72 months
Safety Issue:
Description:DRSS2 is defined as the time from randomization to the first documented local recurrence with visceral lesion or distant metastasis with visceral lesion or secondary systemic malignancy with visceral lesion, whichever occurs first, as assessed by the investigator. For DRSS2, only disease recurrence with visceral lesion is counted as an event.
Measure:DFS According to Participant Programmed Cell Death-Ligand 1 (PD-L1) Expression Status (Positive, Negative) as Assessed by the Investigator
Time Frame:Up to approximately 72 months
Safety Issue:
Description:DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, distant metastasis, secondary systemic malignancy, or death due to any cause, whichever occurs first.
Measure:OS According to Participant PD-L1 Expression Status (Positive, Negative)
Time Frame:Up to approximately 72 months
Safety Issue:
Description:OS is defined as the time from randomization to death due to any cause.
Measure:Plasma Clearance (CL) of Pembrolizumab
Time Frame:Cycles 1 and 2: Pre-dose and 0.5 hours (h) after end of infusion; Cycles 3, 5, 13 and 17: Pre-dose; and 30 days after study treatment discontinuation. Each cycle is 3 weeks long. (Up to approximately 13 months)
Safety Issue:
Description:CL is the volume of plasma from which a substance is completely removed per unit time.
Measure:Volume of Distribution (VD) of Pembrolizumab
Time Frame:Cycles 1 and 2: Pre-dose and 0.5 h after end of infusion; Cycles 3, 5, 13 and 17: Pre-dose; and 30 days after study treatment discontinuation. Each cycle is 3 weeks long. (Up to approximately 13 months)
Safety Issue:
Description:The VD of a drug represents the degree to which a drug is distributed in body tissue rather than the plasma. VD is directly correlated with the amount of drug distributed into tissue; a higher VD indicates a greater amount of tissue distribution.
Measure:Development of Anti-pembrolizumab Antibodies
Time Frame:Cycles 1, 3, 5, 13 and 17: Pre-dose; and 30 days after study treatment discontinuation. Each cycle is 3 weeks long. (Up to approximately 13 months)
Safety Issue:
Description:The number of participants who develop serum anti-pembrolizumab antibodies will be presented.
Measure:European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) Total Score
Time Frame:Baseline and Cycles 1, 5, 9, 13, and 17, treatment discontinuation, 30 day follow up, and annually during post-treatment follow up. Each cycle is 3 weeks long. (Up to approximately 72 months)
Safety Issue:
Description:The QLQ-C30 quality of life (QOL) questionnaire contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea and vomiting, and pain) and single symptom items (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease. Items are scored on a 4-point scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). The QLQC30 also contains 2 global health status scales that use 7-point scale scoring (1=very poor and 7=excellent). The change from baseline in the 2-item global health status/QOL life scale (range: 2-14) will be presented, with a higher score representing a higher QOL.
Measure:Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Index Score
Time Frame:Baseline and Cycles 1, 5, 9, 13, and 17, treatment discontinuation, 30 day follow up, and annually during post-treatment follow up. Each cycle is 3 weeks long. (Up to approximately 72 months)
Safety Issue:
Description:The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer over the previous 7 days. Responses are scored on a 5-point scale (0=Not at all to 4=Very much) and summed to generate an index symptom score. These scores can range from 0 to 36, with a higher score indicating more favorable kidney cancer symptom status.

Details

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

Trial Keywords

  • PD1
  • PD-1
  • PDL1
  • PD-L1
  • Adjuvant

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