Study of Pembrolizumab (MK-3475) Monotherapy in Locally Advanced/Metastatic Renal Cell Carcinoma (MK-3475-427/KEYNOTE-427)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of monotherapy pembrolizumab (MK-3475) in participants with renal cell carcinoma (RCC). There will be two cohorts in this study: Cohort A will consist of participants with clear cell (cc) RCC and Cohort B will consist of participants with non-clear cell (ncc) RCC.

Official Title
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A Phase II Single-arm, Open-label Monotherapy Clinical Trial of Pembrolizumab (MK-3475) in Locally Advanced/Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-427)

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort A (clear cell RCC cohort) participant must have histologically confirmed diagnosis of clear cell RCC or RCC with clear cell component (with or without sarcomatoid features). Cohort B (non-clear cell RCC cohort) participant must have histologically confirmed diagnosis of non-clear cell RCC (with or without sarcomatoid features). Participants with tumors that have a component of clear cell histology are not eligible for inclusion in Cohort B. Has locally advanced/metastatic disease, i.e., newly diagnosed Stage IV RCC per American Joint Committee on Cancer (AJCC) or have recurrent disease. Has measurable disease per RECIST 1.1 as assessed by BICR. Has received no prior systemic therapy for advanced RCC. Prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed >12 months prior to allocation. Must provide adequate tissue for biomarker analysis for Cohorts A and B from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Participants receiving bone resorptive therapy (including but not limited to bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks prior to treatment allocation. Has Karnofsky Performance Status (KPS) ≥70%, as assessed within 10 days prior to treatment allocation. Demonstrates adequate organ function. 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 drug. Male participants of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug. Exclusion Criteria: Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to allocation, has had major surgery within 4 weeks or radiation therapy within 2 weeks prior to allocation, or who has not recovered (i.e., ≤ Grade 1 or to Baseline) from AEs due to prior treatment. Had prior treatment with any anti-programmed cell death 1 (anti-PD-1), or anti-programmed cell death ligand 1 (PD-L1), or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms. Examples of such antibodies include antibodies against indoleamine-2,3-dioxygenase (IDO), PD-L1, interleukin 2 receptors (IL-2R), glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy exceeding 10 mg daily dose of prednisone or equivalent or any other form of immunosuppressive therapy within 7 days prior to allocation, except in the case of central nervous system (CNS) metastases (see below). Has an active autoimmune disease requiring systemic treatment within the past 2 years OR a documented history of clinically severe autoimmune disease. Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, such as breast cancer in situ, that has undergone potentially curative therapy are acceptable. Has known active CNS metastases and/or carcinomatous meningitis. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has an active infection requiring systemic therapy. Has a known history of Human Immunodeficiency Virus (HIV) infection. Has known history of Hepatitis B or known active Hepatitis C. Has received a live virus vaccine within 30 days of allocation. Has had a prior solid organ transplant. 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 drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Clear Cell RCC<br>Participants with clear cell RCC receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 doses (approximately 24 months). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Cohort B: Non-clear Cell RCC<br>Participants with non-clear cell RCC receive pembrolizumab 200 mg IV Q3W for up to 35 doses (approximately 24 months). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). | Up to approximately 52 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | For participants who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR with confirmation. The DOR as assessed using RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented. | Up to approximately 66 months | 
| Disease Control Rate (DCR) | DCR is defined as the percentage of participants who have achieved CR, PR, or Stable Disease (SD) for at least 6 months based on assessments by the BICR per RECIST 1.1. CR is defined as disappearance of all target lesions, PR is defined as at least a 30% decrease in the sum of diameters of target lesions, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. | Up to approximately 66 months | 
| Progression-free Survival (PFS) | PFS is defined as the time from first dose of study treatment to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. | Up to approximately 66 months | 
| Overall Survival | OS was defined as the time from first dose of study treatment to death due to any cause | Up to approximately 66 months | 
| Number of Participants Who Experienced an Adverse Event (AE) | An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. | Up to approximately 27 months | 
| Number of Participants Who Discontinued Study Drug Due to an AE | An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. | Up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1(PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)