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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)

NCT03867084

Description:

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).

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-937
  • SECONDARY ID: 2018-004800-20
  • SECONDARY ID: MK-3475-937
  • SECONDARY ID: KEYNOTE-937
  • NCT ID: NCT03867084

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475Pembrolizumab
PlaceboPlacebo

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
PembrolizumabExperimentalParticipants receive intravenous (IV) pembrolizumab at 200 mg on Day 1 of each 21-day cycle for up to 17 cycles.
  • Pembrolizumab
PlaceboPlacebo ComparatorParticipants receive IV placebo on Day 1 of each 21-day cycle for up to 17 cycles.
  • Placebo

Eligibility 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 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 male, contraceptive use should be consistent with local regulations.

          -  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 that required steroids or has current
             pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has dual active Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection at study
             entry.

          -  Has dual active HBV infection and Hepatitis D Virus (HDV) at the study entry.

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

          -  Has a 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.

          -  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 had an allogenic tissue/solid organ transplant.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recurrence-Free Survival (RFS)
Time Frame:Up to ~3 years
Safety Issue:
Description:RFS is defined as the time from randomization to first documentation of disease recurrence (local, regional, or distant) as assessed by BICR, or death due to any cause (both cancer and non-cancer causes of death), whichever occurs first.

Secondary Outcome Measures

Measure:Percentage of Participants who Experience an Adverse Event (AE)
Time Frame:Up to ~6 years
Safety Issue:
Description: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.
Measure:Percentage of Participants who Discontinue Study Treatment due to an AE
Time Frame:Up to ~1 year
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline and time of last patient reported outcome (PRO) assessment (up to ~5 years)
Safety Issue:
Description: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.
Measure:Change from Baseline in EORTC QLQ-Hepatocellular Carcinoma Module (EORTC QLQ-HCC18) Scale Score
Time Frame:Baseline and time of last PRO assessment (up to ~5 years)
Safety Issue:
Description: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.
Measure:Time to Deterioration (TTD) in the EORTC-QLQ-C30, Combined GHS / QoL Scale Score
Time Frame:Time of last PRO assessment (up to ~5 years)
Safety Issue:
Description:The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Per protocol, the TTD in the combined GHS/QoL scale score will be reported, defined as the time to first onset of a ≥10 point decrease from baseline.
Measure:Time to Deterioration (TTD) in the EORTC QLQ-HCC18 Scale Score
Time Frame:Time of last PRO assessment (up to ~5 years)
Safety Issue:
Description:The EORTC QLQ-HCC18 is an HCC-specific questionnaire, administered in addition to the EORTC QLQ-C30. The TTD in EORTC QLQ-HCC18 scale score will be reported, defined as the time to first onset of a ≥10 point decrease from baseline.
Measure:Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Health Utility Score
Time Frame:Baseline and time of last PRO assessment (up to ~5 years)
Safety Issue:
Description: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.

Details

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

Trial Keywords

  • Programmed Cell Death 1 (PD-1, PD1)
  • Programmed Cell Death Ligand 1 (PD-L1, PDL1)
  • Checkpoint Inhibitor
  • Immunotherapy
  • Adjuvant

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