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)

Brief Summary

Official Title: “Phase I Study of Single Agent MK-3475 in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma”

This study will be done in 6 parts. In Part A the dose of intravenous (IV) pembrolizumab (MK-3475) will be escalated to find 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). Part B of the study will explore the safety, tolerability, and efficacy of the drug in participants with advanced or metastatic MEL and compare every 2 week to every 3 week dosing. Part C of the study will explore the safety, tolerability, and efficacy of the drug in participants with non-small cell lung carcinoma (NSCLC) that is locally advanced or metastatic. Part D of the study will explore the low and high doses of study drug identified in Parts A and B in participants with advanced or metastatic MEL. Part E (closed with Amendment 7) will explore low, medium, and high doses of study drug in combination with standard chemotherapy in participants with locally advanced or metastatic NSCLC. Part F will explore low and high doses of study drug in treatment-naive and previously-treated participants with NSCLC with programmed cell death 1 ligand (PD-L1) gene expression. In Parts D and F and some of Part B participants will be randomized to one dose level. The primary hypotheses are the following: that pembrolizumab has acceptable safety and tolerability; and that pembrolizumab shows a clinically meaningful response rate (RR) or disease-control rate (DCR) in participants with melanoma (ipilimumab-refractory or not), and a clinically meaningful RR in participants with NSCLC, especially a clinically meaningful RR in those participants with either cancer, whose tumors express PD-L1.

  • Study Type: Interventional
  • Study Design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
  • Study Primary Completion Date: July 2016

Detailed Clinical Trial Description

Part F (NSCLC) is the only part currently enrolling participants.

Interventions Used in this Clinical Trial

  • Drug: Pembrolizumab 1 mg/kg
    • IV infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
  • Drug: Pembrolizumab 3 mg/kg
    • IV infusion over 30 minutes on Day 1 of each cycle, at dose of 3 mg/kg
  • Drug: Pembrolizumab 10 mg/kg
    • IV infusion over 30 minutes on Day 1 of each cycle (every 2 or 3 weeks depending on study arm) at a dose of 10 mg/kg.
  • Drug: Pembrolizumab MEL
    • IV infusion over 30 minutes on Day 1 of each cycle
  • Drug: Pembrolizumab NSCLC
    • IV infusion over 30 minutes on Day 1 of each cycle
  • Drug: Pembrolizumab MEL Low Dose
    • IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Drug: Pembrolizumab MEL High Dose
    • IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Drug: Pembrolizumab NSCLC Low Dose
    • IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Drug: Pembrolizumab NSCLC High Dose
    • IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation
  • Drug: Pembrolizumab NSCLC Medium Dose
    • IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation

Arms, Groups and Cohorts in this Clinical Trial

  • Experimental: Part A: Pembrolizumab 1 mg/kg (Closed)
    • Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
  • Experimental: Part A: Pembrolizumab 3 mg/kg (Closed)
    • Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 3 mg/kg
  • Experimental: Part A: Pembrolizumab 10 mg/kg (Closed)
    • Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at dose of 1 mg/kg
  • Experimental: Part B: Pembrolizumab MEL (Closed)
    • Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle.
  • Experimental: Part C: Pembrolizumab NSCLC (Closed)
    • Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle
  • Experimental: Part D: Pembrolizumab MEL Low Dose (Closed)
    • participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Experimental: Part D: Pembrolizumab MEL High Dose (Closed)
    • Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Experimental: Part E: Pembrolizumab NSCLC Low Dose (Closed)
    • Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Experimental: Part E: Pembrolizumab NSCLC Med. Dose (Closed)
    • Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Experimental: Part E: Pembrolizumab NSCLC High Dose (Closed)
    • Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Experimental: Part F: Pembrolizumab NSCLC PD-L1 Low Dose
    • Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation
  • Experimental: Part F: Pembrolizumab NSCLC PD-L1 High Dose
    • Participants receive pembrolizumab IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation

Outcome Measures for this Clinical Trial

Primary Measures

  • Number of participants experiencing dose-limiting toxicities (DLTs)
    • Time Frame: Cycle 1 (28 days)
      Safety Issue?: Yes
  • Number of participants experiencing clinical and laboratory adverse events (AEs)
    • Time Frame: First dose to 30 days post last dose
      Safety Issue?: Yes
  • Number of all study participants who demonstrate a response rate (RR)
    • Time Frame: Weeks 12 and 24
      Safety Issue?: No
  • Number of MEL participants who demonstrated a response rate (RR) and/or disease control rate (DCR)
    • Time Frame: Weeks 12 and 24
      Safety Issue?: No
  • Number of NSCLC participants who demonstrated a response rate (RR)
    • Time Frame: Week 9 and Week 18
      Safety Issue?: No
  • Change from Baseline in candidate biomarker expression levels in MELS and NSCLC participants
    • Time Frame: Week 12 and Week 24 (MEL), Week 9 and Week 18 (NSCLC)
      Safety Issue?: No

Secondary Measures

  • The area under the curve (AUC) of plasma concentration of drug against time after administration of pembrolizumab (Part A)
    • Time Frame: Pre-dose, 30 minutes, 6, 24, and 48 hours post-dose, and on Days 8, 15, 22, and 29 of Cycle 1; pre- and post-dose on Day 1 of every other subsequent 14-day cycle up to 12 months
      Safety Issue?: No
  • Maximum concentration (Cmax) after first dose interval of pembrolizumab
    • Time Frame: Part A, Cycle 1 + Day 1 of Cycle 2 and then every 14-day cycle for up to 12 months; Part B Q2W, Cycles 1 and 3; Part B Q3W, Cycles 1 and 2; Part C, Cycles 1 and 2; Part D, Cycles 1 and 6; Part E, Cycles 1 and 6; Part F, Cycles 1 and 6.
      Safety Issue?: No
  • Time at which maximum concentration (Tmax) occurs for pembrolizumab (Part A)
    • Time Frame: Pre-dose, 30 minutes, 6, 24, and 48 hours post-dose, and on Days 8, 15, 22, and 29 of Cycle 1; pre- and post-dose on Day 1 of every other subsequent 14-day cycle up to 12 months
      Safety Issue?: No
  • Lowest plasma concentration (C[trough]) of pembrolizumab
    • Time Frame: Part A, Cycle 1+ Day 1 Cycle 2, and each 14-day cycle for up to 12 mo.; Part B Q2W, Cycles 1,3,7 + every 4 cycles for 12 mo.; Parts B/C Q3W, Cycles 1, 2, 5 + every 4 cycles for 12 mo.; Parts D/E/F, Cycles 1, 2, 3, 6, 8 + every 4 cycles for up to 2 yrs.
      Safety Issue?: No
  • Terminal half-life (t1/2) of pembrolizumab (Parts B, C, D, E and F)
    • Time Frame: Pre-dose, 30 minutes, 6, 24, and 48 hours post-dose, and on Days 8, 15, 22, and 29 of Cycle 1; pre- and post-dose on Day 1 of every other subsequent 14-day cycle starting with Cycle 2 for up to 12 months.
      Safety Issue?: No
  • Progression free survival (PFS) in MEL and NSCLC participants
    • Time Frame: From first documented response up to 2 years
      Safety Issue?: No
  • Overall survival (OS) in MEL and NSCLC participants
    • Time Frame: From first dose of study drug until death or lost to follow-up (up to 2 years)
      Safety Issue?: No
  • Duration of response (DR) in MEL and NSCLC participants
    • Time Frame: From first documented response up to 2 years
      Safety Issue?: No

Criteria for Participation in this Clinical Trial

Inclusion criteria (Part F is the only part currently enrolling participants).

  • 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 F, 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.

Exclusion criteria (Part F is the only part currently enrolling participants)

  • 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 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.
  • History of acute diverticulitis, intra-abdominal abscess, GI obstruction, 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • Merck Sharp & Dohme Corp.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Director, Study Director, Merck Sharp & Dohme Corp.

Citations Reporting on Results

Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2. Epub 2014 Jul 15.

Source

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http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01295827