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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) (KEYNOTE-001)

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ClinicalTrials.gov Identifier: NCT01295827
Recruitment Status : Completed
First Posted : February 15, 2011
Last Update Posted : December 21, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE February 10, 2011
First Posted Date  ICMJE February 15, 2011
Last Update Posted Date December 21, 2018
Actual Study Start Date  ICMJE March 4, 2011
Actual Primary Completion Date November 5, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 9, 2016)
  • Number of participants experiencing dose-limiting toxicities (DLTs) [ Time Frame: Up to 28 days in Cycle 1 ]
  • Number of participants experiencing clinical and laboratory adverse events (AEs) [ Time Frame: Up to 30 days post last dose ]
  • Number of all study participants who demonstrate a response rate (RR) [ Time Frame: Weeks 9, 12, 18, and 24 ]
  • Number of MEL participants who demonstrated a response rate (RR) and/or disease control rate (DCR) [ Time Frame: Weeks 12 and 24 ]
  • Number of NSCLC participants who demonstrated a response rate (RR) [ Time Frame: Week 9 and Week 18 ]
  • 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) ]
Original Primary Outcome Measures  ICMJE
 (submitted: February 14, 2011)
  • Number of participants experiencing dose-limiting toxicities. [ Time Frame: Cycle 1 (28 days) ]
  • Number of participants experiencing clinical and laboratory adverse events (AEs). [ Time Frame: First dose to 30 days post last dose ]
Change History Complete list of historical versions of study NCT01295827 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2016)
  • 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 ]
  • 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. ]
  • 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 ]
  • 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. ]
  • 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. ]
  • Progression free survival (PFS) in MEL and NSCLC participants [ Time Frame: From first documented response up to 5 years ]
  • 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 5 years) ]
  • Duration of response (DR) in MEL and NSCLC participants [ Time Frame: From first documented response up to 5 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2011)
  • The area under the curve (AUC) of plasma concentration of drug against time after administration of MK-3475 [ 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 Days 1 and 14 of every other subsequent 14-day cycle up to 12 months ]
  • Maximum concentration (Cmax) after first dose interval of MK-3475 [ 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 Days 1 and 14 of every other subsequent 14-day cycle up to 12 months ]
  • Time at which maximum concentration (Tmax) occurs for MK-3475 [ 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 Days 1 and 14 of every other subsequent 14-day cycle up to 12 months ]
  • Lowest plasma concentration (C[trough]) of MK-3475 [ 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 Days 1 and 14 of every other subsequent 14-day cycle up to 12 months ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE Phase I Study of Single Agent Pembrolizumab (MK-3475) in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (KEYNOTE 001)
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cancer, Solid Tumor
Intervention  ICMJE
  • 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
  • Drug: Pembrolizumab NSCLC 200 mg
    IV infusion over 30 minutes every 3 weeks
    Other Name: KEYTRUDA®
Study Arms
  • 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
    Intervention: Drug: Pembrolizumab 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
    Intervention: Drug: Pembrolizumab 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
    Intervention: Drug: Pembrolizumab 10 mg/kg
  • Experimental: Part B: Pembrolizumab MEL (Closed)
    Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle.
    Intervention: Drug: Pembrolizumab MEL
  • Experimental: Part C: Pembrolizumab NSCLC (Closed)
    Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle
    Intervention: Drug: Pembrolizumab NSCLC
  • 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
    Intervention: Drug: Pembrolizumab MEL Low Dose
  • 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
    Intervention: Drug: Pembrolizumab MEL High Dose
  • 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
    Intervention: Drug: Pembrolizumab NSCLC Low Dose
  • 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
    Intervention: Drug: Pembrolizumab NSCLC Medium Dose
  • 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
    Intervention: Drug: Pembrolizumab NSCLC High Dose
  • Experimental: Part F: Pembrolizumab NSCLC PD-L1 Low Dose (Closed)
    Participants receive pembrolizumab IV infusion over 30 minutes every 3 weeks at dose determined during dose escalation. All participants were changed over to a 200 mg fixed dose of pembrolizumab IV every 3 weeks based on analysis of safety and efficacy data.
    Interventions:
    • Drug: Pembrolizumab NSCLC Low Dose
    • Drug: Pembrolizumab NSCLC 200 mg
  • Experimental: Part F: Pembrolizumab NSCLC PD-L1 High Dose (Closed)
    Participants receive pembrolizumab IV infusion over 30 minutes every 2 or 3 weeks at dose determined during dose escalation. All participants were changed over to a 200 mg fixed dose of pembrolizumab IV every 3 weeks based on analysis of safety and efficacy data.
    Interventions:
    • Drug: Pembrolizumab NSCLC High Dose
    • Drug: Pembrolizumab NSCLC 200 mg
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 30, 2015)
1260
Original Estimated Enrollment  ICMJE
 (submitted: February 14, 2011)
32
Actual Study Completion Date December 11, 2018
Actual Primary Completion Date November 5, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
  • 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 (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.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Australia,   Canada,   France,   Italy,   Korea, Republic of,   Norway,   Spain,   Taiwan,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT01295827
Other Study ID Numbers  ICMJE P07990
MK-3475-001 ( Other Identifier: Merck Protocol Number )
2011-002371-42 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP