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A Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy or Immunotherapy in Participants With Non-small Cell Lung Cancer (MK-3475-021/KEYNOTE-021)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02039674
Recruitment Status : Completed
First Posted : January 17, 2014
Results First Posted : December 2, 2017
Last Update Posted : November 8, 2022
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Description
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Brief Summary:
The purpose of this study is to determine the safety, tolerability, and efficacy of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic non-small cell lung cancer (NSCLC).

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Carcinoma Biological: Pembrolizumab Drug: Paclitaxel Drug: Carboplatin Biological: Bevacizumab Drug: Pemetrexed Biological: Ipilimumab Drug: Erlotinib Drug: Gefitinib Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 267 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of MK-3475 (SCH900475) in Combination With Chemotherapy or Immunotherapy in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Carcinoma
Study Start Date : February 21, 2014
Actual Primary Completion Date : November 7, 2016
Actual Study Completion Date : October 18, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Part 1 Cohort A2 (Pembro2mg/kg+Paclitaxel [Pa]+Carboplatin [C])
Cohort A participants receive pembrolizumab (2 mg/kg) via intravenous (IV) infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (Aare Under the Curve [AUC] 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Paclitaxel
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: ABRAXANE®

Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®
Experimental: Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B])
Cohort B2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Paclitaxel
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: ABRAXANE®

Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®

Biological: Bevacizumab
IV on Day 1 of each 3-week cycle
Other Name: AVASTIN®
Experimental: Part 1 Cohort C2 (Pembro 2mg/kg+Pemetrexed [Pe]+C)
Cohort C2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®

Drug: Pemetrexed
IV on Day 1 of each 3-week cycle
Other Name: ALIMTA®
Experimental: Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I])
Cohort D1 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Biological: Ipilimumab
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: YERVOY®
Experimental: Part 1 Cohort E (Pembro 2mg/kg+Erlotinib)
Cohort E participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS erlotinib (150 mg) via oral tablet once a day on every day of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Erlotinib
Orally tablet once daily
Other Name: TARCEVA®
Experimental: Part 1 Cohort F (Pembro 2mg/kg+Gefitinib)
Cohort F participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS gefitinib (250 mg) via oral tablet once a day on every day of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Gefitinib
Oral tablet once daily
Other Name: IRESSA®
Experimental: Part 2 Cohort G+ (Pembro 200mg+C+Pe)
Cohort G+ participants receive pembrolizumab (200 mg) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®

Drug: Pemetrexed
IV on Day 1 of each 3-week cycle
Other Name: ALIMTA®
Experimental: Part 2 Cohort H (Pembro+I)
Cohort H participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle (at the recommended Phase II dose determined in Cohort D).
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Biological: Ipilimumab
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: YERVOY®
Experimental: Part 1 Cohort A10 (Pembro+Paclitaxel [Pa]+Carboplatin [C])
Cohort A10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Paclitaxel
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: ABRAXANE®

Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®
Experimental: Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B])
Cohort B10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Paclitaxel
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: ABRAXANE®

Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®

Biological: Bevacizumab
IV on Day 1 of each 3-week cycle
Other Name: AVASTIN®
Experimental: Part 1 Cohort C10 (Pembro 10mg/kg+Pemetrexed [Pe]+C)
Cohort C10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®

Drug: Pemetrexed
IV on Day 1 of each 3-week cycle
Other Name: ALIMTA®
Experimental: Part 2 Cohort G- (Placebo+C+Pe)
Cohort G- participants receive placebo (normal saline solution) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS.
 Drug: Carboplatin
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: PARAPLATIN®

Drug: Pemetrexed
IV on Day 1 of each 3-week cycle
Other Name: ALIMTA®
Experimental: Part 1 Cohort D2 (Pembro 10mg/kg+Ipilimumab [I])
Cohort D2 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (3 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Biological: Ipilimumab
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: YERVOY®
Experimental: Part 1 Cohort D4 (Pembro 2mg/kg+Ipilimumab [I])
Cohort D1 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
 Biological: Pembrolizumab
IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
Other Names:
  • MK-3475
  • KEYTRUDA®
  • SCH 900475

Biological: Ipilimumab
IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
Other Name: YERVOY®


Outcome Measures
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Primary Outcome Measures :
  1. Part 2 Cohorts G+ and G-: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
    ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR).

  2. Part 2 Cohorts D4 and H: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
    For participants who demonstrated a confirmed response (Complete Response [CR]: Disappearance of all target lesions or Partial Response [PR]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR.

  3. All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) [ Time Frame: Cycle 1 (Up to 21 days) ]
    DLTs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. A DLT was defined as any of the following events: Grade 4 non-hematologic toxicity (not laboratory); Grade 4 hematologic toxicity lasting ≥7 days; Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and diarrhea) lasting >3 days despite optimal supportive care; Any Grade 3 or Grade 4 non-hematologic laboratory value requiring treatment or hospitalization, or persisting for >1 week; Febrile neutropenia Grade 3 or Grade 4; Qualifying thrombocytopenia <25,000/mm^3; Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Missing >10% of erlotinib or gefitinib doses as a result of adverse events (AEs) during the DLT window of observation; or Grade 5 toxicity.


Secondary Outcome Measures :
  1. Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS) [ Time Frame: Up to approximately 2 years ]
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. PFS was assessed by BICR.

  2. Part 2 Cohorts G+ and G-: Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
    OS was defined as the time from randomization to death due to any cause.

  3. Part 2 Cohorts G+ and G-: Duration of Response (DOR) [ Time Frame: Up to approximately 2 years ]
    For participants who demonstrated a confirmed response (Complete Response [CR]: Disappearance of all target lesions or Partial Response [PR]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR.


Eligibility Criteria
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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.


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

Inclusion Criteria:

  • Stage IIIb/IV NSCLC
  • Disease progression >1 year after completing adjuvant therapy for Stage I-IIIA disease and no systemic therapy for the recurrent disease
  • Resolution of any toxic effects (excepting alopecia) of the most recent therapy
  • At least one radiographically measurable lesion
  • Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status scale
  • Female participants of reproductive potential must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start)
  • Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 120 days after the last dose of study therapy and for up to 180 days after the last dose of chemotherapeutic agents or tyrosine kinase inhibitors

Exclusion Criteria:

  • Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of pembrolizumab
  • Expected to require any other form of antineoplastic therapy while on study
  • Is on chronic systemic steroid therapy or on any other form of immunosuppressive medication
  • Has received a live-virus vaccination within 30 days of planned treatment start
  • Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
  • History of a hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid tumor, unless the participant has undergone potentially curative therapy with no evidence of that disease for 5 years
  • Active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
  • Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed)
  • Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms
  • Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 3 weeks of the first dose of study medication
  • Radiation therapy to lung >30 Gy within 6 months of first dose of study medication
  • Prior tyrosine kinase inhibitor therapy or palliative radiation within 7 days of first dose of study medication
  • Active infection requiring therapy
  • History of Human Immunodeficiency Virus (HIV)
  • Active Hepatitis B or C
  • Symptomatic ascites or pleural effusion
  • Interstitial lung disease or pneumonitis requiring oral or IV glucocorticoids
  • Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
  • Psychiatric disorders and substance (drug/alcohol) abuse
Contacts and Locations
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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): NCT02039674


Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
Layout table for investigator information
Study Director: Medical Director Merck Sharp & Dohme LLC
  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:
Study Protocol and Statistical Analysis Plan  [PDF] April 20, 2020

More Information
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Additional Information:

Publications of Results:

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

Layout table for additonal information
Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT02039674    
Other Study ID Numbers: 3475-021
MK-3475-021 ( Other Identifier: Merck Protocol Number )
KEYNOTE-021 ( Other Identifier: Merck )
First Posted: January 17, 2014    Key Record Dates
Results First Posted: December 2, 2017
Last Update Posted: November 8, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pd
URL: http://engagezone.msd.com/ds_documentation.php
Keywords provided by Merck Sharp & Dohme LLC:
PD-1
PD1
Programmed Cell Death-1
Programmed Cell Death 1
Chemotherapy
Pemetrexed
 Paclitaxel
Bevacizumab
Erlotinib
Gefitinib
Ipilimumab
Carboplatin
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Paclitaxel
Bevacizumab
 Carboplatin
Pembrolizumab
Pemetrexed
Erlotinib Hydrochloride
Ipilimumab
Gefitinib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Angiogenesis Inhibitors
Angiogenesis Modulating Agents