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Trial record 1 of 1 for:    Adjuvant immunotherapy with anti-PD-1 monoclonal antibody Pembrolizumab (MK-3475) versus placebo after complete resection of high-risk Stage III melanoma: A randomized, double- blind Phase 3 trial of the EORTC Melanoma Group
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Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02362594
Recruitment Status : Active, not recruiting
First Posted : February 13, 2015
Results First Posted : January 4, 2019
Last Update Posted : February 12, 2019
Sponsor:
Collaborator:
European Organisation for Research and Treatment of Cancer
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE February 9, 2015
First Posted Date  ICMJE February 13, 2015
Results First Submitted Date  ICMJE December 10, 2018
Results First Posted Date  ICMJE January 4, 2019
Last Update Posted Date February 12, 2019
Actual Study Start Date  ICMJE July 16, 2015
Actual Primary Completion Date January 8, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 10, 2019)
  • Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among All Participants [ Time Frame: 6 months ]
    RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants in both treatment arms of Part 1.
  • Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among Participants With PD-L1-positive Tumor Expression [ Time Frame: 6 months ]
    RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants with PD-L1-positive tumors in both treatment arms of Part 1.
Original Primary Outcome Measures  ICMJE
 (submitted: February 9, 2015)
  • Recurrence-free survival (RFS) for All Participants [ Time Frame: Up to 3 years ]
  • RFS for Participants with PD-L1-positive Tumor Expression [ Time Frame: Up to 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2018)
  • Distant Metastases-free Survival (DMFS) in All Participants [ Time Frame: Up to 10 years ]
    DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants in both treatment arms.
  • Distant Metastases-free Survival (DMFS) for Participants With PD-L1-positive Tumor Expression [ Time Frame: Up to 10 years ]
    Description: DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants with PD-L1-positive tumors in both treatment arms.
  • Overall Survival (OS) for All Participants [ Time Frame: Up to 10 years ]
    OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants in both treatment arms.
  • Overall Survival (OS) for Participants With PD-L1-positive Tumor Expression [ Time Frame: Up to 10 years ]
    OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants with PD-L1-positive tumors in both treatment arms.
  • Number of Participants Who Experienced At Least 1 Adverse Event (AE) [ Time Frame: Up to 22 months ]
    An AE is defined as "any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment". An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who experienced at least 1 AE was reported for all participants in each treatment arm.
  • Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to 22 months ]
    An AE is defined as "any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment". An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who discontinued study treatment due to an AE was reported for all participants in each treatment arm.
  • Clearance (CL) of Pembrolizumab [ Time Frame: Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks. ]
    Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab CL, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following IV pembrolizumab administration. Samples were not collected and this analysis was not performed.
  • Volume of Distribution (V) of Pembrolizumab [ Time Frame: Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks. ]
    Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab V, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. Samples were not collected and this analysis was not performed.
  • Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment [ Time Frame: Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks. ]
    Pre- and post-baseline serum samples from participants treated with pembrolizumab were analyzed for ADA by means of a neutralizing antibody assay which assessed the ability of ADA to block (neutralize) binding of pembrolizumab to Programmed Cell Death-1 (PD-1) protein. Overall immunogenicity was defined as the number of treatment emergent positive participants based on the total number of evaluable participants (treatment emergent positive, non-treatment emergent positive and negative immunogenicity status).
Original Secondary Outcome Measures  ICMJE
 (submitted: February 9, 2015)
  • Distant Metastases-free Survival (DMFS) in All Participants [ Time Frame: Up to 3 years ]
  • DMFS for Participants with PD-L1-positive Tumor Expression [ Time Frame: Up to 3 years ]
  • Overall Survival (OS) in All Participants [ Time Frame: Up to 3 years ]
  • OS in for Participants with PD-L1-positive Tumor Expression [ Time Frame: Up to 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)
Official Title  ICMJE Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Melanoma Group
Brief Summary This study will assess whether post-surgery therapy with pembrolizumab improves recurrence-free survival (RFS) as compared to placebo for high-risk participants with melanoma (Stage IIIA [> 1 mm metastasis], IIIB and IIIC). The study will also assess whether pembrolizumab improves RFS versus placebo in the subgroup of participants with programmed cell death-ligand 1 (PD-L1)-positive tumor expression. Participants will be stratified for stage of disease and region and then will be randomly assigned to receive either pembrolizumab or placebo as post-surgery therapy in Part 1. In Part 2, participants who experience a disease recurrence are eligible for pembrolizumab treatment (if treated with placebo in Part 1) or pembrolizumab rechallenge (if treated with pembrolizumab in Part 1).
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 Melanoma
Intervention  ICMJE
  • Biological: pembrolizumab
    Pembrolizumab 200 mg administered intravenously (IV) on Day 1 of each 21-day cycle
    Other Names:
    • KEYTRUDA®
    • MK-3475
  • Drug: placebo
    Normal saline solution administered IV on Day 1 of each 21-day cycle
Study Arms  ICMJE
  • Experimental: Pembrolizumab
    In Part 1, participants receive pembrolizumab 200 mg intravenously (IV) as post-surgery therapy every 3 weeks (Q3W) for up to 1 year. During Part 2, participants with documented recurrence may receive optional re-treatment with pembrolizumab Q3W for up to 2 years or disease progression.
    Intervention: Biological: pembrolizumab
  • Placebo Comparator: Placebo
    In Part 1, participants receive placebo IV as post-surgery therapy Q3W. During Part 2, participants with documented recurrence who received placebo in Part 1 may receive optional treatment with pembrolizumab Q3W for up to 2 years or disease progression.
    Intervention: Drug: placebo
Publications *

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 23, 2017)
1019
Original Estimated Enrollment  ICMJE
 (submitted: February 9, 2015)
900
Estimated Study Completion Date  ICMJE July 31, 2023
Actual Primary Completion Date January 8, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Completely resected Stage III melanoma
  • Tumor tissue available for evaluation of PD-L1 expression
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Adequate organ function
  • No prior therapy for melanoma except surgery for primary melanoma lesions (or previously treated with interferon for thick primary melanomas without evidence of lymph node involvement are eligible)
  • Female participants of childbearing potential should be willing to use adequate methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
  • Male participants should agree to use an adequate method of birth control starting with the first dose of study therapy through 120 days after the last dose of study medication

Exclusion criteria:

  • Mucosal or ocular melanoma
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • History of or current interstitial lung disease
  • History of hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years
  • Active autoimmune disease that has required systemic treatment in past 2 years
  • Active infection requiring therapy
  • Unstable hyperthyroidism or hypothyroidism
  • Diagnosis of immunodeficiency
  • Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
  • Known history of human immunodeficiency virus (HIV), active Hepatitis B or C
  • Treatment with live vaccine within 30 days prior to the first dose of study medication are not eligible
  • Prior treatment with any anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody or anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent, or prior participation in any Merck pembrolizumab clinical trial
  • Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study medication
  • Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication
  • Participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial without prospective Institutional Review Board approval (by chair or designee) is given
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Australia,   Austria,   Belgium,   Canada,   Denmark,   Finland,   France,   Germany,   Israel,   Italy,   Japan,   Netherlands,   New Zealand,   Norway,   Poland,   Portugal,   Russian Federation,   Serbia,   Spain,   Sweden,   Switzerland,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT02362594
Other Study ID Numbers  ICMJE 3475-054
1325-MG ( Other Identifier: European Organisation for Research and Treatment of Cancer )
2014-004944-37 ( EudraCT Number )
163277 ( Registry Identifier: JAPIC-CTI )
KEYNOTE-054 ( Other Identifier: Merck )
MK-3475-054 ( Other Identifier: Merck )
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 European Organisation for Research and Treatment of Cancer
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date January 2019

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