Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)

• ClinicalTrials.gov Identifier: NCT03553836
• Recruitment Status: Active, not recruiting
• First Posted: June 12, 2018
• Last Update Posted: November 12, 2020
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Tracking Information

• First Submitted Date: June 1, 2018
• First Posted Date: June 12, 2018
• Last Update Posted Date: November 12, 2020
• Actual Study Start Date: September 12, 2018
• Estimated Primary Completion Date: October 26, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 12, 2020)

Recurrence-free Survival (RFS) [ Time Frame: Up to 4 Years ]

RFS is defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause.

Original Primary Outcome Measures (submitted: June 1, 2018)

Recurrence-free Survival (RFS) [ Time Frame: Up to 4 Years ]

RFS is defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 for immune-based therapeutics (iRECIST 1.1) or death due to any cause.

Current Secondary Outcome Measures (submitted: October 12, 2020)

• Distant Metastasis-free Survival (DMFS) [ Time Frame: Up to 9 Years ]
  DMFS is defined as the time from randomization to the first diagnosis of a distant metastasis per RECIST 1.1. Distant metastasis refers to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes.
• Overall Survival (OS) [ Time Frame: Up to 15 Years ]
  OS is the time from randomization to death due to any cause.
• Incidence of Adverse Events (AEs) [ Time Frame: From time of signing the informed consent form (ICF) until the end of follow-up (up to approximately 39 months) ]
  Percentage of participants experiencing an AE defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy.
• Incidence of Discontinuations [ Time Frame: From time of signing the ICF until the end of study treatment (up to approximately 36 months) ]
  Percentage of participants discontinuing study drug due to an AE.

Original Secondary Outcome Measures (submitted: June 1, 2018)

• Distant Metastasis-free Survival (DMFS) [ Time Frame: Up to 9 Years ]
  DMFS is defined as the time from randomization to the first diagnosis of a distant metastasis per iRECIST 1.1. Distant metastasis refers to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes.
• Overall Survival (OS) [ Time Frame: Up to 15 Years ]
  OS is the time from randomization to death due to any cause.
• Incidence of Adverse Events (AEs) [ Time Frame: From time of signing the informed consent form (ICF) until the end of follow-up (up to approximately 39 months) ]
  Percentage of participants experiencing an AE defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy.
• Incidence of Discontinuations [ Time Frame: From time of signing the ICF until the end of study treatment (up to approximately 36 months) ]
  Percentage of participants discontinuing study drug due to an AE.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)
• Official Title: Adjuvant Therapy With Pembrolizumab Versus Placebo in Resected High-risk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE-716)
• Brief Summary: This 2-part study will evaluate the safety and efficacy of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma. Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design for up to 17 cycles (each cycle = 21 days). Participants who receive placebo or who stop treatment after receiving 17 cycles of pembrolizumab in Part 1, do not experience disease recurrence within 6 months of completing pembrolizumab in Part 1, and do not stop treatment with pembrolizumab for disease recurrence or intolerability, may be eligible to receive up to 35 additional cycles of pembrolizumab in Part 2 in an open-label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Biological: Pembrolizumab
  Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
  Other Names:

  • KEYTRUDA®
  • MK-3475
• Other: Placebo
  Administered as an IV infusion every 3 weeks (Q3W)

Study Arms

• Experimental: Pembrolizumab
  Pediatric participants receive 2 mg/kg (200 mg maximum) pembrolizumab by intravenous (IV) infusion every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in a double-blind design in Part 1. Adult participants receive 200 mg pembrolizumab by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in a double-blind design in Part 1. Participants that complete 17 cycles of pembrolizumab and experience disease recurrence may be eligible to receive additional cycles of pembrolizumab in Part 2 in an open-label design. In Part 2, participants will receive up to 17 cycles (up to ~1 year) of pembrolizumab for local/distant recurrence following disease resection or up to 35 cycles (up to ~2 years) of pembrolizumab for unresectable disease recurrence. Participants with distant metastasis who undergo complete resection will receive 17 cycles (up to ~1 year) of pembrolizumab but can receive up to 35 cycles (up to ~2 years) of pembrolizumab under certain circumstances.
  Intervention: Biological: Pembrolizumab
• Placebo Comparator: Placebo
  Participants receive saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in a double-blind design in Part 1. Participants that complete 17 cycles of placebo and experience disease recurrence may be eligible to receive pembrolizumab in Part 2 in an open-label design. In Part 2, participants will receive up to 17 cycles (up to ~1 year) of pembrolizumab for local/distant recurrence following disease resection or up to 35 cycles (up to ~2 years) of pembrolizumab for disease that cannot be resected or metastatic disease.
  Interventions:

  • Biological: Pembrolizumab
  • Other: Placebo

• Publications *: Luke JJ, Ascierto PA, Carlino MS, Gershenwald JE, Grob JJ, Hauschild A, Kirkwood JM, Long GV, Mohr P, Robert C, Ross M, Scolyer RA, Yoon CH, Poklepovic A, Rutkowski P, Anderson JR, Ahsan S, Ibrahim N, M Eggermont AM. KEYNOTE-716: Phase III study of adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma. Future Oncol. 2020 Jan;16(3):4429-4438. doi: 10.2217/fon-2019-0666. Epub 2019 Dec 24.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: June 1, 2018): 954
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 12, 2033
• Estimated Primary Completion Date: October 26, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion:

• Has surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer (AJCC) 8th edition guidelines
• Has not been previously treated for melanoma beyond complete surgical resection
• Has ≤12 weeks between final surgical resection and randomization
• Has no evidence of metastatic disease on imaging as determined by investigator
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale or Lansky Play-Performance Scale (LPS) score ≥50 for participants ≤16 years old, or a Karnofsky Performance Scale (KPS) score ≥50 for participants >16 and <18 years old
• Has recovered adequately from toxicity and/or complications from surgery prior to study start
• Female participants must not be pregnant or breastfeeding, and must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment if they are a woman of childbearing potential (WOCBP)

Exclusion:

• Has a known additional malignancy that is progressing or has required active antineoplastic therapy (including hormonal) within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• Has recovered adequately from major surgery or the toxicity and/or complications from the intervention prior to starting study treatment
• WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Has received prior therapy with an 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 with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)
• Has received prior systemic anti-cancer therapy for melanoma including investigational agents
• 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 the first dose of study treatment
• Has severe hypersensitivity (≥Grade 3) to any excipients of pembrolizumab
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known active Hepatitis C virus (defined as Hepatitis C virus ribonucleic acid ((RNA)) [qualitative] is detected) infection
• Has a history of active tuberculosis (Bacillus tuberculosis)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• 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 allogeneic tissue/solid organ transplant

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT03553836
• Other Study ID Numbers: 3475-716; 2018-000669-35 ( EudraCT Number ); MK-3475-716 ( Other Identifier: Merck Protocol Number ); KEYNOTE-716 ( Other Identifier: Merck ); 205203 ( Registry Identifier: JAPIC-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

• 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: Merck Sharp & Dohme Corp.
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

• PRS Account: Merck Sharp & Dohme Corp.
• Verification Date: November 2020