Immunologic Determinants of Response to Pembrolizumab (MK-3475) in Advanced Melanoma (MK-3475-161/KEYNOTE-161)
Condition: Advanced Melanoma
MeSH terms: Melanoma
Intervention: pembrolizumab
Intervention description: 200 mg by IV infusion Q3W for up to 24 months
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD-1); PD1; Programmed Cell Death-Ligand 1 (PD-L1); Programmed Cell Death-Ligand 2 (PD-L2); PDL1; PDL2

Summary:

      In this study, participants with advanced melanoma will be treated with pembrolizumab
      (MK-3475) and their tumors and blood will be analyzed for changes related to pembrolizumab
      therapy.

      The primary hypotheses are that participants who respond to pembrolizumab have:

        1. a higher fraction of cytotoxic tumor-infiltrating T-lymphocytes (FCT) at baseline
           compared to those who do not respond to pembrolizumab

        2. a higher fold-increase in FCT compared to baseline than those who do not respond to
           pembrolizumab

        3. a higher Average Specific Cytotoxic T-lymphocyte Frequency Ratio (ASCTFR) compared to
           those who do not respond to pembrolizumab
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has a histologically confirmed diagnosis of unresectable stage III or metastatic
             melanoma not amenable to local therapy

          -  Has testing for a BRAF mutation prior to study entry

          -  Has measurable disease per RECIST 1.1 as assessed by the investigator/radiology

          -  Has resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or
             less (except alopecia). If the participant received major surgery or radiation therapy
             of >30 Gray units, they must have recovered from the toxicity and/or complications
             from the intervention

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within
             10 days of study start

          -  A female participant is eligible to participate if she is not pregnant or
             breastfeeding, and at least one of the following conditions applies: is not a woman of
             childbearing potential (WOCBP) OR is a WOCBP and agrees to use a contraceptive method,
             consistent with local regulations regarding the methods of contraception for those
             participating in clinical studies, during the treatment period and for at least 120
             days after the last dose of study treatment

          -  A male participant is eligible to participate if he agrees not to donate sperm PLUS to
             be abstinent from heterosexual intercourse as their preferred and usual lifestyle OR
             agree to use contraception, consistent with local regulations regarding the methods of
             contraception for those participating in clinical studies, during the treatment period
             and for at least 120 days after the last dose of study treatment

        Exclusion Criteria:

          -  Has disease that is suitable for local therapy administered with curative intent

          -  Has a history of interstitial lung disease

          -  Has a positive pregnancy test within 72 hours before the first dose of study therapy

          -  Has received prior therapy with an anti-Programmed Cell Death Protein 1 (PD-1),
             anti-Programmed Cell Death-Ligand 1 (PD-L1), anti-Programmed Cell Death-Ligand 2
             (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell
             receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137)

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to study start

          -  Has received prior radiotherapy within 2 weeks of start of study therapy

          -  Has received a live vaccine within 30 days prior to the first dose of study therapy

          -  Has received transfusion of blood products (including platelets or red blood cells) or
             administration of colony stimulating factors (including granulocyte colony stimulating
             factor [G-CSF], granulocyte macrophage colony stimulating factor [GMCSF] or
             recombinant erythropoietin) within 4 weeks prior to study start

          -  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 therapy

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             or any other form of immunosuppressive therapy within 7 days prior the first dose of
             study therapy

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years with the exception of basal cell and squamous cell carcinoma
             of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ
             (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially
             curative therapy

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis

          -  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 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 [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
             detected) infection

          -  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 known psychiatric or substance abuse disorders that would interfere with
             cooperating with the requirements of the study

          -  Is pregnant or breastfeeding or expecting to conceive or father children starting with
             the screening visit through 120 days after the last dose of study therapy