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)
- Trial ID
- 2022-501971-24-00
- Protocol
- MK-3475-937
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to compare **Recurrence-Free Survival (RFS)** and **Overall Survival (OS)** in participants with **hepatocellular carcinoma** who have achieved a complete radiological response following surgical resection or local ablation. This comparison is clinically significant as it evaluates the potential of pembrolizumab as an adjuvant therapy to improve survival outcomes in this patient population.
Secondary objectives include:
- Evaluating the safety and tolerability of pembrolizumab.
- Comparing time to deterioration (TTD) and score change from baseline in global quality of life (QoL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) global health status/QoL scale and EORTC QLQ-HCC18.
- Characterizing health utilities using the EuroQoL-5 Dimension Questionnaire, 5-Level (EQ-5D-5L) health utility scores.
Participants
The clinical trial involves a total of **690 participants** diagnosed with **hepatocellular carcinoma (HCC)**, focusing on adjuvant treatment. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. The trial population was selected based on specific inclusion criteria, such as having a diagnosis of HCC confirmed by radiological or pathological means, adequate organ function, and a Child-Pugh class A liver score. Participants must have no radiologic evidence of disease prior to enrollment and must have undergone surgical resection or local ablation with a complete radiological response. The trial includes individuals with controlled hepatitis B and requires female participants to adhere to strict contraceptive measures if of childbearing potential. The study does not exclude vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the safety and efficacy of **pembrolizumab** versus placebo as adjuvant therapy in participants with **hepatocellular carcinoma** (HCC) who have achieved a complete radiological response following surgical resection or local ablation. The trial aims to compare **recurrence-free survival** (RFS) and **overall survival** (OS) as primary endpoints, with secondary endpoints including the percentage of participants experiencing adverse events, discontinuation due to adverse events, and changes in quality of life scores.
The trial is expected to last until August 2029, with participant recruitment having commenced in May 2019. Participants will be involved in the study for a maximum treatment period of 51 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have a confirmed diagnosis of HCC, adequate organ function, and no radiologic evidence of disease prior to enrollment. Participants must also have a Child-Pugh class A liver score and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Participants may be terminated early from the study if they experience significant adverse events, fail to adhere to study protocols, or if the investigator deems it necessary for their safety. The trial is conducted under strict regulatory guidelines to ensure the integrity of the data and the safety of the participants. The investigational product, pembrolizumab, is administered via **intravenous infusion**, with a maximum daily dose of 200 mg and a total dose not exceeding 3400 mg over the treatment period. The placebo used in the study is normal saline, serving as a control to evaluate the true efficacy of pembrolizumab in this patient population.
Treatment
The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 3400 mg over the course of the treatment period, which spans up to 51 weeks. Pembrolizumab is a biological product, specifically a protein of other origin, and is manufactured by Merck Sharp & Dohme BV. The medication is identified by the sponsor product code MK-3475 and is authorized under the marketing authorization number EU/1/15/1024/002. The administration schedule and participant compliance are closely monitored to ensure adherence to the dosing regimen.
The study also includes a **placebo** treatment, which is a normal saline solution used as a comparator to KEYTRUDA. The placebo is designed to mimic the administration of the experimental drug without containing any active pharmaceutical ingredient. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The use of placebo allows for the evaluation of the safety and efficacy of pembrolizumab by providing a control group for comparison. Compliance with the placebo administration is similarly monitored to ensure the integrity of the study results.
Efficacy
The efficacy of the clinical trial will be assessed by comparing **Recurrence-Free Survival (RFS)** and **Overall Survival (OS)** between participants receiving Pembrolizumab and those receiving a placebo. These primary endpoints will provide critical data on the effectiveness of Pembrolizumab as an adjuvant therapy in participants with hepatocellular carcinoma who have achieved a complete radiological response following surgical resection or local ablation. Secondary endpoints include the percentage of participants experiencing adverse events, the percentage discontinuing treatment due to adverse events, and changes from baseline in quality of life scores as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC QLQ-Hepatocellular Carcinoma Module (EORTC QLQ-HCC18), and the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Health Utility Score.
Inclusion and Exclusion Criteria
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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 06 May 2019 | 18 |
 Denmark | Not Recruiting | 06 May 2019 | 14 |
 France | Not Recruiting | 06 May 2019 | 30 |
 Germany | Not Recruiting | 06 May 2019 | 33 |
 Hungary | Not Recruiting | 06 May 2019 | 25 |
 Ireland | Not Recruiting | 06 May 2019 | 8 |
 Italy | Not Recruiting | 06 May 2019 | 30 |
 Norway | Not Recruiting | 06 May 2019 | 20 |
 Poland | Not Recruiting | 06 May 2019 | 22 |
 Spain | Not Recruiting | 06 May 2019 | 36 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 51 | PRD4323105 |
Placebo to Keytruda - Normal saline | Placebo | N/A | — | — | — | N/A |