Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001)
Condition: Cancer, Solid Tumor
MeSH terms: Carcinoma; Melanoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Pembrolizumab
Intervention description: IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Intervention MeSH terms: Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1260.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melanoma; Carcinoma; Cancer; Advanced cancer; Metastatic cancer; Metastatic melanoma; Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)

Summary:

      The present study has 5 parts. In Parts A and A1, the dose of intravenous (IV) pembrolizumab
      (MK-3475) will be escalated from 1 to 10 mg/kg to determine the maximum tolerated dose (MTD)
      and recommended Phase 2 dose (RP2D) for participants with a histologically- or
      cytologically-confirmed diagnosis of any type of carcinoma or melanoma (MEL) by evaluating
      the Dose Limiting Toxicities (DLTs). Following completion of the dose escalation, additional
      patients will be enrolled in Part A2 to further define pharmacokinetic characteristics. Part
      B of the study will investigate the safety, tolerability, and efficacy of pembrolizumab (2
      mg/kg and 10 mg/kg) in participants with advanced or metastatic MEL and compare every 2 week
      dosing (Q2W) to every 3 week dosing (Q3W). Part C of the study will investigate the safety,
      tolerability, and efficacy of pembrolizumab administered at 10 mg/kg Q3W in participants with
      non-small cell lung carcinoma (NSCLC) that is locally advanced or metastatic. Part D of the
      study will investigate the low and high doses of study drug identified in Parts A and B (2
      mg/kg and 10 mg/kg) administered Q3W in participants with advanced or metastatic MEL. Part E
      (closed with Amendment 7) was planned to investigate low, medium, and high doses of
      pembrolizumab in combination with standard chemotherapy in participants with locally advanced
      or metastatic NSCLC. Part F will investigate low and high doses of pembrolizumab (2 mg/kg and
      10 mg/kg) administered Q2W or Q3W in treatment-naive and previously-treated participants with
      NSCLC with programmed cell death 1 ligand (PD-L1) gene expression. The primary hypotheses are
      the following: that pembrolizumab will have acceptable safety and tolerability; that
      pembrolizumab will show a clinically meaningful response rate (RR) or disease-control rate
      (DCR) in participants with melanoma (ipilimumab-refractory or not) and NSCLC, and that
      pembrolizumab will show a more clinically meaningful RR in participants with either cancer
      whose tumors express PD-L1.
    

Eligibility criteria:

        Inclusion Criteria

          -  In Part A: Histological or cytological diagnosis of MEL or any type of carcinoma,
             progressive metastatic disease, or progressive locally advanced disease not amenable
             to local therapy. In Parts B and D of the study, histological or cytological diagnoses
             of metastatic MEL with progressive locally advanced or metastatic disease. In Parts C
             and F, histological or cytological diagnosis of NSCLC. In Part F1, participants with
             Stage IV NSCLC without prior systemic therapy may be eligible.

          -  Failure of established standard medical anti-cancer therapies for a given tumor type
             or intolerance to such therapy.

          -  In Parts B, C, D, or F of the study, MEL or NSCLC must be measurable by imaging.

          -  In Part F of the study, NSCLC with PD-L1 gene expression.

          -  Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale.

          -  Adequate organ function.

          -  Female participants of childbearing potential should have a negative urine or serum
             pregnancy test prior to receiving study medication

          -  Female participants of childbearing potential must be willing to use adequate
             contraception from study start, through the course of the study, and for 120 days
             after the last dose of study medication

          -  Male participants of childbearing potential must agree to use adequate contraception
             from the first dose of study medication through 120 days after the last dose of study
             medication

        Exclusion Criteria

          -  Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the
             first dose of study therapy, or not recovered to Common Terminology Criteria for
             Adverse Events (CTCAE) Grade 1 or better from the adverse events caused by therapy
             administered more than 4 weeks prior to first dose.

          -  Participation in a study of an investigational agent or using an investigational
             device within 30 days of administration of pembrolizumab, with the exception of
             participants in the follow-up phase.

          -  Other form(s) of antineoplastic therapy anticipated during the period of the study.

          -  History of non-infectious pneumonitis requiring treatment with steroids, or has a
             history of interstitial lung disease.

          -  Medical condition that requires chronic systemic steroid therapy, or on any other form
             of immunosuppressive medication, excepting use of inhaled steroids.

          -  Risk factors for bowel obstruction or bowel perforation (including a history of acute
             diverticulitis, intra-abdominal abscess, abdominal carcinomatosis).

          -  History of a hematologic malignancy, malignant primary brain tumor, malignant sarcoma,
             or another malignant primary solid tumor, unless no evidence of that disease for 5
             years.

          -  Active central nervous system (CNS) metastases and/or carcinomatous meningitis.

          -  Previous severe hypersensitivity reaction to another monoclonal antibody (mAb).

          -  Active autoimmune disease or a documented history of autoimmune disease or syndrome
             that requires systemic steroids or immunosuppressive agents, except vitiligo or
             resolved childhood asthma/atopy.

          -  Prior therapy with another anti-programmed cell death (PD)-1 agent or previously
             enrolled in any pembrolizumab trial.

          -  Active infection requiring therapy.

          -  Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface
             Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid
             [HCV RNA] (qualitative) is detected).

          -  Regular use of illicit drugs or a recent history (within the last year) of substance
             abuse (including alcohol).

          -  Symptomatic ascites or pleural effusion.

          -  Participant is pregnant or breastfeeding, or expecting to conceive or father children
             within the projected duration of the study.