Safety and Efficacy of Pembrolizumab (MK-3475) Versus Placebo as Adjuvant Therapy in Participants With Hepatocellular Carcinoma (HCC) and Complete Radiological Response After Surgical Resection or Local Ablation (MK-3475-937 / KEYNOTE-937)

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of pembrolizumab (MK-3475) versus placebo as adjuvant therapy in participants with hepatocellular carcinoma (HCC) and complete radiological response after surgical resection or local ablation. The primary hypotheses of this study are that adjuvant pembrolizumab is superior to placebo with respect to: 1) recurrence-free survival (RFS) as assessed by blinded independent central review (BICR); and 2) overall survival (OS).

Official Title
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A Phase 3 Double-blinded, Two-arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) Versus Placebo as Adjuvant Therapy in Participants With Hepatocellular Carcinoma and Complete Radiological Response After Surgical Resection or Local Ablation (KEYNOTE-937)

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of HCC by radiological criteria and/or pathological confirmation. Has an eligibility scan (CT of the chest, triphasic CT scan or MRI of the abdomen, and CT or MRI of the pelvis) confirming complete radiological response ≥4 weeks after complete surgical resection or local ablation. Randomization needs to occur within 12 weeks of the date of surgical resection or local ablation. Has no radiologic evidence of disease prior to enrollment. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to Cycle 1, Day 1. Has a Child-Pugh class A liver score (5 to 6 points) within 7 days prior to Cycle 1, Day 1. Has alpha fetoprotein (AFP) concentration lower than 400 ng/mL within 28 days prior to Cycle 1, Day 1. Has controlled hepatitis B (Hep B). Has recovered adequately from toxicity and/or complications from the local intervention (surgical resection or local ablation) prior to starting study treatment. If female, is not pregnant or breastfeeding, and at least one of the following conditions applies: 1) Is not a woman of childbearing potential (WOCBP); or 2) Is a WOCBP and using a contraceptive method that is highly effective or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (a WOCBP must have a negative pregnancy test within 72 hours before the first dose of study treatment). If undergoing surgical resection, has submitted a tumor tissue sample during Screening. Has adequate organ function. Exclusion Criteria: Has a known additional malignancy that is progressing or has required active antineoplastic treatment (including hormonal) or surgery within the past 3 years. Has had esophageal or gastric variceal bleeding within the last 6 months. Has clinically apparent ascites on physical examination. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Has received local therapy to liver ablation other than with radiofrequency or microwave ablation. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Has an active infection requiring systemic therapy. Has dual active Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection at study entry. Has a known history of human immunodeficiency virus (HIV) infection. Has known active tuberculosis (TB; Bacillus tuberculosis). Has received prior therapy with an 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 (eg, CTLA-4, OX-40, CD137). Has received prior systemic anti-cancer therapy for HCC including investigational agents. Is receiving any of the following prohibited concomitant therapies:1) Antineoplastic systemic chemotherapy or biological therapy; 2) Immunotherapy not specified in this protocol; 3) Investigational agents other than pembrolizumab; 4) Radiation therapy; 5) Oncological surgical therapy; or systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is suspected to have an immunologic etiology. 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 Cycle 1, Day 1. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Cycle 1, Day 1. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Has an active autoimmune disease that has required systemic treatment in past 2 years. 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.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>Participants receive intravenous (IV) pembrolizumab at 200 mg on Day 1 of each 21-day cycle for up to 17 cycles. | Biological: Pembrolizumab<br>* IV infusion of Pembrolizumab 200 mg.<br>* Other names: MK-3475;|
| Placebo Comparator: Placebo<br>Participants receive IV placebo on Day 1 of each 21-day cycle for up to 17 cycles. | Drug: Placebo<br>* IV infusion of 0.9% normal saline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-Free Survival (RFS) | RFS is defined as the time from randomization to first documentation of disease recurrence (local, regional, or distant) as assessed by BICR or by pathology consistent with HCC if required per the site's standard of care, or death due to any cause (both cancer and non-cancer causes of death), whichever occurs first. | Up to  6 years | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to  8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Experience an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined. | Up to  8 years | 
| Percentage of Participants who Discontinue Study Treatment Due to an AE | An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined. | Up to  1 year | 
| Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Combined Global Health Status (GHS) / Quality of Life (QoL) Scale Score | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients, including a combined GHS/QoL (Items 29 and 30) scale. Per protocol, the change from baseline in the combined GHS/QoL score (range: 0-100) will be reported. Higher overall GHS/QoL scores indicate higher GHS/QoL. | Baseline and time of last patient reported outcome (PRO) assessment (up to  5 years) | 
| Change from Baseline in EORTC QLQ-Hepatocellular Carcinoma Module (EORTC QLQ-HCC18) Scale Score | The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30, with scores ranging from 0-100. Higher scores indicate more severe symptoms/problems. Change from baseline in the EORTC QLQ-HCC18 scale score will be reported. | Baseline and time of last PRO assessment (up to  5 years) | 
| Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Health Utility Score | The EQ-5D-5L measured health-related outcomes, assessing 5 health state dimensions (mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression) on a 5-point scale from 1 (no problem) to 5 (extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates their general state of health. | Baseline and time of last PRO assessment (up to  5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death 1 (PD-1, PD1), Programmed Cell Death Ligand 1 (PD-L1, PDL1), Checkpoint Inhibitor, Immunotherapy, Adjuvant