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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 : April 2, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
The present study has 5 parts. In Part A, the dose of intravenous (IV) pembrolizumab (MK-3475) will be escalated 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). Part B of the study will investigate the safety, tolerability, and efficacy of pembrolizumab 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 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 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 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), that pembrolizumab will show a clinically meaningful RR in participants with NSCLC, and that pembrolizumab will show a more clinically meaningful RR in participants with either cancer whose tumors express PD-L1.

Condition or disease Intervention/treatment Phase
Cancer, Solid Tumor Biological: Pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1260 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : March 4, 2011
Actual Primary Completion Date : November 5, 2018
Actual Study Completion Date : December 11, 2018


Arm Intervention/treatment
Experimental: Part A Dose Escalation: Pembrolizumab 1 mg/kg-Solid Tumor
Participants receive pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of each cycle, at a dose of 1 mg/kg. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part A Dose Escalation: Pembrolizumab 3 mg/kg-Solid Tumor
Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle, at a dose of 3 mg/kg. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part A Dose Escalation: Pembrolizumab 10 mg/kg-Solid Tumor
Participants receive pembrolizumab IV infusion over 30 minutes on Day 1 of each cycle, at a dose of 1 mg/kg. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part B: Pembrolizumab 2 mg/kg-MEL
Participants receive pembrolizumab IV at a dose of 2 mg/kg Q2W. As of Amendment 3, participants receive dosing Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part B: Pembrolizumab 10 mg/kg-MEL
Participants receive pembrolizumab IV at a dose of 10 mg/kg Q2W. As of Amendment 7, participants receive dosing either Q2W or Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part C: Pembrolizumab 10 mg/kg-NSCLC
Participants receive pembrolizumab IV at a dose of 10 mg/kg Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part D: Pembrolizumab 2 mg/kg-MEL
Participants receive pembrolizumab IV at a dose of 2 mg/kg Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part D: Pembrolizumab 10 mg/kg-MEL
Participants receive pembrolizumab IV at a dose of 10 mg/kg Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part E: Pembrolizumab 2 mg/kg-NSCLC (Not Enrolled)
Participants receive pembrolizumab IV at a dose of 2 mg/kg Q3W.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part E: Pembrolizumab 5 mg/kg-NSCLC (Not Enrolled)
Participants receive pembrolizumab IV at a dose of 5 mg/kg Q3W.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part E: Pembrolizumab 10 mg/kg-NSCLC (Not Enrolled)
Participants receive pembrolizumab IV at a dose of 10 mg/kg Q3W.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part F-1: Pembrolizumab 10 mg/kg-NSCLC TrT Naïve PD-L1
Participants receive pembrolizumab IV at a dose of 10 mg/kg Q2W or Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part F-2: Pembrolizumab 10 mg/kg-NSCLC PD-L1
Participants receive pembrolizumab IV at a dose of 10 mg/kg Q2W or Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®

Experimental: Part F-3: Pembrolizumab 2 mg/kg-NSCLC PD-L1
Participants receive pembrolizumab IV at a dose of 2 mg/kg Q3W. As of Amendment 10, all remaining and ongoing participants will be treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Biological: Pembrolizumab
IV infusion over 30 minutes on Day 1 of each cycle, administered according to dose selection or randomization.
Other Names:
  • MK-3475
  • KEYTRUDA®




Primary Outcome Measures :
  1. Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) in Melanoma Participants (Part A) [ Time Frame: Up to 28 days in Cycle 1 ]
  2. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to ~90 months ]
  3. Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Melanoma Participants [ Time Frame: Up to ~53 months ]
  4. Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~53 months ]

Secondary Outcome Measures :
  1. Overall Response Rate (ORR) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Programmed Death-Ligand 1 (PD-L1)-Positive Melanoma Participants [ Time Frame: Up to ~53 months ]
  2. Overall Response Rate (ORR) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Programmed Death-Ligand 1 (PD-L1)-Positive Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~53 months ]
  3. Area Under the Concentration-Time Curve of Pembrolizumab from Time 0 to Infinity (AUC 0-inf) in Melanoma Participants (Part A) [ Time Frame: Cycle 1: Pre-dose and post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) ]
  4. Maximum Concentration (Cmax) of Pembrolizumab in Melanoma Participants (Part A) [ Time Frame: Cycle 1: Pre-dose and post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) ]
  5. Time to Maximum Concentration (Tmax) of Pembrolizumab in Melanoma Participants (Part A) [ Time Frame: Cycle 1: Pre-dose and post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) ]
  6. Terminal Half-Life (t ½) of Pembrolizumab in Melanoma Participants (Part A) [ Time Frame: Cycle 1: Pre-dose and post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days) ]
  7. Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Melanoma and Non-Small Cell Lung Cancer (NSCLC) Participants (Parts B, C, D and F) [ Time Frame: Pre-dose on Day 1 of a cycle, every 4 cycles up to discontinuation (up to ~79 months). A cycle = 21 days. ]
  8. Disease Control Rate (DCR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Melanoma Participants [ Time Frame: Up to ~53 months ]
  9. Duration of Response (DOR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology Analysis (IRO) in Melanoma Participants [ Time Frame: Up to ~53 months ]
  10. Progression Free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology Analysis (IRO) in Melanoma Participants [ Time Frame: Up to ~53 months ]
  11. Overall Survival (OS) in Melanoma Participants [ Time Frame: Up to ~90 months ]
  12. Disease Control Rate (DCR) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants [ Time Frame: Up to 53 months ]
  13. Duration of Response (DOR) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants [ Time Frame: Up to ~53 months ]
  14. Progression Free Survival (PFS) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants [ Time Frame: Up to ~53 months ]
  15. Disease Control Rate (DCR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~53 months ]
  16. Duration of Response (DOR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology Analysis (IRO) in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to 53 months ]
  17. Progression Free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology Analysis (IRO) in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~53 months ]
  18. Overall Survival (OS) in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~90 months ]
  19. Disease Control Rate (DCR) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~53 months ]
  20. Duration of response (DOR) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~53 months ]
  21. Progression Free Survival (PFS) According to immune-related Response Criteria (irRC) as Assessed by Investigator in Non-Small Cell Lung Cancer (NSCLC) Participants [ Time Frame: Up to ~53 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01295827


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01295827     History of Changes
Other Study ID Numbers: P07990
MK-3475-001 ( Other Identifier: Merck Protocol Number )
2011-002371-42 ( EudraCT Number )
First Posted: February 15, 2011    Key Record Dates
Last Update Posted: April 2, 2019
Last Verified: March 2019
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
Melanoma
Carcinoma
Cancer
Advanced cancer
Metastatic cancer
Metastatic melanoma
PD-1
PD1
Additional relevant MeSH terms:
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Carcinoma
Melanoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents