Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Pembrolizumab; Placebo
Intervention description: Administered as an intravenous (IV) infusion every 3 weeks (Q3W); Administered as an IV infusion every 3 weeks (Q3W)
Intervention MeSH terms: Pembrolizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking description: Participants and Investigators will be blinded in Part 1 and unblinded in Part 2, if done.
Enrollment: 976.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1(PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

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 every 3 weeks
      (Q3W) for up to 17 cycles/~1 year (each cycle = 21 days). Participants who complete the
      initial treatment of 17 cycles of pembrolizumab in Part 1 and experience disease recurrence
      may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg
      Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2 in an open label design.
      Participants who complete the initial treatment of placebo and experience disease recurrence
      may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35
      cycles (up to ~2 years) 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.

      Per protocol, response/ progression or adverse events (AEs) during re-challenge/switch-over
      in Part 2 will not be counted towards the RFS outcome measure or safety outcome measures
      respectively.
    

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 women 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

          -  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 (non-infectious) 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