Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)
Condition: Malignant Melanoma
MeSH terms: Melanoma
Intervention: Pembrolizumab; Carboplatin; Paclitaxel; Dacarbazine; Temozolomide
Intervention description: IV infusion; Carboplatin per institutional standard; Paclitaxel per institutional standard; Dacarbazine per institutional standard; Temozolomide per institutional standard
Intervention MeSH terms: Paclitaxel; Carboplatin; Pembrolizumab; Temozolomide; Dacarbazine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 540.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)

Summary:

      This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or
      standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after
      prior therapy.

      Initial Treatment Period:

      Participants were initially randomized to receive either low-dose (2 mg/kg) pembrolizumab,
      higher dose (10 mg/kg) pembrolizumab or Investigator-choice chemotherapy (ICC). The four
      standard chemotherapy choices were: carboplatin + paclitaxel, paclitaxel alone, dacarbazine,
      or temozolomide. The randomization to either pembrolizumab or ICC was conducted in an
      open-label fashion.

      The starting pembrolizumab dose was initially blinded to Investigators and participants until
      Amendment 03. With Amendment 03, all ongoing pembrolizumab participants were to be treated
      with open label, fixed dose pembrolizumab 200 mg, instead of a weight-based dosing of
      pembrolizumab.

      Switch-to-Pembrolizumab Treatment Period:

      Participants who were initially randomized to receive ICC and experienced progressive disease
      (PD) may have been eligible to switch to receiving pembrolizumab provided they met
      protocol-specified requirements for switching. Qualified participants were re-randomized to
      receive either pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg in a double-blind fashion.
      Participants who qualified to switch to pembrolizumab must have completed a washout period of
      ≥28 days from last dose of chemotherapy before receiving pembrolizumab. With Amendment 03,
      all switched-to-pembrolizumab participants were to be treated with open-label, fixed dose
      pembrolizumab 200 mg instead of a weight-based dosing of pembrolizumab.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed diagnosis of unresectable Stage III or
             metastatic MEL not amenable to local therapy

          -  Participants must be refractory to ipilimumab

          -  Participants with BRAF gene mutant melanoma must have had a prior treatment regimen
             that included vemurafenib, dabrafenib, or an approved BRAF gene and/or
             mitogen-activated protein kinase (MEK) protein inhibitor

          -  Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy
             specimen (or specimen obtained within 60 days of consenting)

          -  Radiographically measurable disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

        Exclusion Criteria:

          -  Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to
             the first dose of study drug, or not recovered from the AEs due to cancer therapies
             administered more than 4 weeks earlier

          -  Disease progression within 24 weeks of last dose of ipilimumab

          -  Participating or has participated in a study of an investigational agent or using an
             investigational device within 30 days of the first dose of study drug

          -  Expected to require any other form of systemic or localized antineoplastic therapy
             while on study

          -  Chronic systemic steroid therapy within 2 weeks before the planned date for first dose
             randomized treatment or on any other form of immunosuppressive medication

          -  Known history of any other than the current malignancy excepting adequately treated
             basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ
             cervical cancer, breast cancer, or other in situ cancers

          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis

          -  Active autoimmune disease or a history of autoimmune disease or syndrome that requires
             systemic steroids or immunosuppressive agents

          -  Prior treatment with any other anti-programmed cell death (PD) agent

          -  Active infection requiring systemic therapy

          -  Known history of Human Immunodeficiency Virus (HIV)

          -  Active Hepatitis B or Hepatitis C

          -  Regular user (including recreational use of) illicit drugs or had a recent history
             (within the last year) of substance abuse (including alcohol)

          -  Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study through 120 days after last dose of study drug