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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03867084
Recruitment Status : Recruiting
First Posted : March 7, 2019
Last Update Posted : September 21, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE March 6, 2019
First Posted Date  ICMJE March 7, 2019
Last Update Posted Date September 21, 2020
Actual Study Start Date  ICMJE May 28, 2019
Estimated Primary Completion Date June 30, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2019)
  • Recurrence-Free Survival (RFS) [ Time Frame: Up to ~4 years ]
    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.
  • Overall Survival (OS) [ Time Frame: Up to ~6 years ]
    OS is defined as the time from randomization to death due to any cause.
Original Primary Outcome Measures  ICMJE
 (submitted: March 6, 2019)
  • Recurrence-Free Survival (RFS) [ Time Frame: Up to ~3 years ]
    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.
  • Overall Survival (OS) [ Time Frame: Up to ~6 years ]
    OS is defined as the time from randomization to death due to any cause.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2020)
  • Percentage of Participants who Experience an Adverse Event (AE) [ Time Frame: Up to ~6 years ]
    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.
  • Percentage of Participants who Discontinue Study Treatment Due to an AE [ Time Frame: Up to ~1 year ]
    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.
  • 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 ~7 years) ]
    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.
  • 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 ~7 years) ]
    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.
  • Time to Deterioration (TTD) in the EORTC-QLQ-C30, Combined GHS / QoL Scale Score [ Time Frame: Time of last PRO assessment (up to ~7 years) ]
    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.
  • Time to Deterioration (TTD) in the EORTC QLQ-HCC18 Scale Score [ Time Frame: Time of last PRO assessment (up to ~7 years) ]
    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.
  • 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 ~7 years) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2019)
  • Percentage of Participants who Experience an Adverse Event (AE) [ Time Frame: Up to ~6 years ]
    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.
  • Percentage of Participants who Discontinue Study Treatment Due to an AE [ Time Frame: Up to ~1 year ]
    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.
  • 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) ]
    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.
  • 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) ]
    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.
  • 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) ]
    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.
  • Time to Deterioration (TTD) in the EORTC QLQ-HCC18 Scale Score [ Time Frame: Time of last PRO assessment (up to ~5 years) ]
    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.
  • 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) ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
Brief Summary 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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Hepatocellular Carcinoma
Intervention  ICMJE
  • Biological: Pembrolizumab
    IV infusion of Pembrolizumab 200 mg.
    Other Names:
    • KEYTRUDA®
    • MK-3475
  • Drug: Placebo
    IV infusion of 0.9% normal saline.
Study Arms  ICMJE
  • Experimental: Pembrolizumab
    Participants receive intravenous (IV) pembrolizumab at 200 mg on Day 1 of each 21-day cycle for up to 17 cycles.
    Intervention: Biological: Pembrolizumab
  • Placebo Comparator: Placebo
    Participants receive IV placebo on Day 1 of each 21-day cycle for up to 17 cycles.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 6, 2019)
950
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2025
Estimated Primary Completion Date June 30, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Brazil,   Canada,   China,   Denmark,   France,   Germany,   Hong Kong,   Hungary,   Ireland,   Israel,   Italy,   Japan,   Korea, Republic of,   Malaysia,   New Zealand,   Norway,   Poland,   Russian Federation,   Spain,   Sweden,   Switzerland,   Taiwan,   Thailand,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03867084
Other Study ID Numbers  ICMJE 3475-937
2018-004800-20 ( EudraCT Number )
MK-3475-937 ( Other Identifier: Merck Protocol Number )
KEYNOTE-937 ( Other Identifier: Merck )
194786 ( Registry Identifier: JAPAC-CTI )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP