Brief Summary
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.
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.
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)
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.
With Protocol Amendment 02 (dated 04 Sep 2019), the secondary study objectives for the evaluation of pharmacokinetic (PK) parameters and the presence of pembrolizumab antidrug antibodies (ADA) were reclassified as tertiary study objectives.
With Protocol Amendment 02 (dated 04 Sep 2019), the secondary study objectives for the evaluation of pharmacokinetic (PK) parameters and the presence of pembrolizumab antidrug antibodies (ADA) were reclassified as tertiary study objectives.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Renal Cell Carcinoma
Eligibility Criteria
Inclusion Criteria:
* Has histologically confirmed diagnosis of renal cell carcinoma (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 no evidence of disease (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-programmed cell death-ligand 2 (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
* Has histologically confirmed diagnosis of renal cell carcinoma (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 no evidence of disease (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-programmed cell death-ligand 2 (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
Inclusion Criteria
Inclusion Criteria:
* Has histologically confirmed diagnosis of renal cell carcinoma (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 no evidence of disease (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
* Has histologically confirmed diagnosis of renal cell carcinoma (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 no evidence of disease (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
Gender
All
Gender Based
false
Keywords
Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Adjuvant
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03142334
Org Class
Industry
Org Full Name
Merck Sharp & Dohme LLC
Org Study Id
3475-564
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 3, 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)
Primary Outcomes
Outcome Description
DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, distant kidney cancer metastasis(es), or death due to any cause, whichever occurs first. Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastasis status (M0 versus M1 no evidence of disease (NED) by investigator) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 versus 1), United States (US) participant (Yes versus No) within M0 group by investigator was used to report hazard ratio (HR) and 95% confidence intervals (CIs).
Outcome Measure
Disease-free Survival (DFS) as Assessed by the Investigator
Outcome Time Frame
Up to approximately 42 months (database cutoff date 14 Dec 2020)
Secondary Ids
Secondary Id
173704
Secondary Id
MK-3475-564
Secondary Id
KEYNOTE-564
Secondary Id
U1111-1275-8289
Secondary Id
2016-004351-75
Secondary Outcomes
Outcome Description
OS was defined as the time from randomization to death due to any cause.
Outcome Time Frame
Up to approximately 72 months
Outcome Measure
Overall Survival (OS)
Outcome 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.
Outcome 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)
Outcome Measure
Number of Participants Who Experienced an Adverse Event (AE)
Outcome 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.
Outcome Time Frame
Up to approximately 12 months
Outcome Measure
Number of Participants Who Discontinued Study Drug Due to an AE
Outcome 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.
Outcome Time Frame
Up to approximately 72 months
Outcome Measure
First Local Disease Recurrence-specific Survival (DRSS1) as Assessed by the Investigator
Outcome Description
DRSS2 is defined as the time from randomization to the first documented local recurrence with visceral lesion or occurrence of distant kidney cancer metastasis(es) with visceral lesion, whichever occurs first, as assessed by the investigator.
Outcome Time Frame
Up to approximately 72 months
Outcome Measure
Second Disease Recurrence-Specific Survival (DRSS2) as Assessed by the Investigator
Outcome Description
EFS is defined as time from randomization to the first documented local recurrence or occurrence of distant kidney cancer metastasis(es) among participants which by BICR were considered disease-free at baseline (M0/M1 NED); or disease progression among participants which by BICR were considered to have baseline disease (M1), or death due to any cause, whichever occurs first.
Outcome Time Frame
Up to approximately 72 months
Outcome Measure
Event-Free Survival (EFS) as Assessed by the Blinded Independent Central Review (BICR)
Outcome Description
DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, or occurrence of distant kidney cancer metastasis(es), or death due to any cause, whichever occurs first. The PD-L1 expression status is based on combined positive score (CPS). If CPS is ≥ 1, PD-L1 expression status is positive and if the CPS is \<1, PD-L1 expression status is negative.
Outcome Time Frame
Up to approximately 72 months
Outcome Measure
DFS According to Participant Programmed Cell Death-Ligand 1 (PD-L1) Expression Status (Positive, Negative) as Assessed by the Investigator
Outcome Description
OS is defined as the time from randomization to death due to any cause. The PD-L1 expression status is based on combined positive score (CPS). If CPS is ≥ 1, PD-L1 expression status is positive and if the CPS is \<1, PD-L1 expression status is negative.
Outcome Time Frame
Up to approximately 72 months
Outcome Measure
OS According to Participant PD-L1 Expression Status (Positive, Negative)
Outcome 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.
Outcome Time Frame
Baseline and Week 52
Outcome Measure
Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) Total Score
Outcome 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. The change from baseline in the FKSI-DRS index score will be presented.
Outcome Time Frame
Baseline and Week 52
Outcome Measure
Change From Baseline in the Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Index Score
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Benjamin Gartrell
Investigator Email
bgartrel@montefiore.org
Investigator Phone
718-405-8404