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Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Participants Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (MK-3475-859/KEYNOTE-859)

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: NCT03675737
Recruitment Status : Active, not recruiting
First Posted : September 18, 2018
Results First Posted : October 12, 2023
Last Update Posted : October 12, 2023
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 evaluate the efficacy of pembrolizumab (MK-3745) in combination with chemotherapy (Cisplatin combined with 5-Fluorouracil [FP regimen] or oxaliplatin combined with capecitabine [CAPOX regimen]) versus placebo in combination with chemotherapy (FP or CAPOX regimens) in the treatment of human epidermal growth factor receptor 2 (HER2) negative advanced gastric or GEJ adenocarcinoma in adult participants.

The primary hypotheses of this study are that pembrolizumab plus chemotherapy is superior to placebo plus chemotherapy in terms of overall survival (OS).


Condition or disease Intervention/treatment Phase
Stomach Neoplasms Biological: Pembrolizumab Drug: Cisplatin Drug: 5-fluorouracil Drug: oxaliplatin Drug: capecitabine Drug: Placebo for Pembrolizumab Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1579 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-blind Clinical Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy as First-line Treatment in Participants With HER2 Negative, Previously Untreated, Unresectable or Metastatic Gastric Orgastroesophageal Junction Adenocarcinoma (KEYNOTE-859)
Actual Study Start Date : November 8, 2018
Actual Primary Completion Date : October 3, 2022
Estimated Study Completion Date : September 28, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Pembrolizumab + Chemotherapy (FP or CAPOX regimen)

Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m^2 IV on Day 1 Q3W and 5-fluorouracil (5FU) 800 mg/m^2/day via continuous IV infusion on Days 1 to 5 Q3W (FP regimen) OR oxaliplatin 130 mg/m^2 IV on Day 1 Q3W + capecitabine 1000 mg/m^2 orally twice a day (BID) on Days 1 to 14 Q3W (CAPOX regimen).

Participants who complete up to 35 administrations of pembrolizumab (approximately 2 years) or achieve a complete response (CR) but experience progression of disease (PD), can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).

 Biological: Pembrolizumab
Administered as an IV infusion on Day 1 Q3W
Other Names:
  • KEYTRUDA®
  • MK-3475

Drug: Cisplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: PLATINOL®

Drug: 5-fluorouracil
Administered as a continuous IV infusion on Days 1-5 Q3W
Other Names:
  • ADRUCIL®
  • 5FU

Drug: oxaliplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: ELOXATIN®

Drug: capecitabine
Administered orally BID on Days 1 to 14 Q3W
Other Name: XELODA®
Active Comparator: Placebo + Chemotherapy (FP or CAPOX regimen)
Participants receive placebo on Day 1 Q3W for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m^2 IV on Day 1 Q3W and 5FU 800 mg/m^2/day via continuous IV infusion on Days 1 to 5 Q3W (FP regimen) OR oxaliplatin 130 mg/m^2 IV on Day 1 Q3W + capecitabine 1000 mg/m^2 orally BID on Days 1 to 14 Q3W (CAPOX regimen).
 Drug: Cisplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: PLATINOL®

Drug: 5-fluorouracil
Administered as a continuous IV infusion on Days 1-5 Q3W
Other Names:
  • ADRUCIL®
  • 5FU

Drug: oxaliplatin
Administered as an IV infusion on Day 1 Q3W
Other Name: ELOXATIN®

Drug: capecitabine
Administered orally BID on Days 1 to 14 Q3W
Other Name: XELODA®

Drug: Placebo for Pembrolizumab
Administered as an IV infusion on Day 1 Q3W


Outcome Measures
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Primary Outcome Measures :
  1. Overall Survival (OS) in All Participants [ Time Frame: Up to 45.9 months ]
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data.

  2. Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 [ Time Frame: Up to 45.9 months ]
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data.

  3. Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 [ Time Frame: Up to 45.9 months ]
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants [ Time Frame: Up to 49.5 months ]
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data.

  2. Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 [ Time Frame: Up to 49.5 months ]
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data.

  3. Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 [ Time Frame: Up to 49.5 months ]
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data.

  4. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants [ Time Frame: Up to 49.5 months ]
    ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR.

  5. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 [ Time Frame: Up to 49.5 months ]
    ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR.

  6. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 [ Time Frame: Up to 49.5 months ]
    ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR.

  7. Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants [ Time Frame: Up to 49.5 months ]
    DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data.

  8. Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 [ Time Frame: Up to 49.5 months ]
    DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data.

  9. Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 [ Time Frame: Up to 49.5 months ]
    DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data.

  10. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to 36.7 months ]
    An AE was defined as any untoward medical occurrence, in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one AE is presented.

  11. Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) [ Time Frame: Up to 33.7 months ]
    An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented.


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.


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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

  • Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with known programmed cell death ligand 1 (PD-L1) expression status
  • Has human epidermal growth factor receptor 2 (HER2) negative cancer
  • Male participants must agree to use contraception during the treatment period and through 95 days after the last dose of chemotherapy, refrain from donating sperm, and be abstinent from heterosexual intercourse, as their preferred and usual lifestyle, and agree to remain abstinent or must agree to use contraception per study protocol unless confirmed to be azoospermic during this period
  • Female participants who are not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) OR is a WOCBP who agrees to use contraception or be abstinent from heterosexual intercourse, as their preferred and usual lifestyle, during the treatment period and through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is last, and agrees not to donate eggs to others or freeze/store for her own use for the purpose of reproduction during this period
  • Has measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by investigator assessment
  • Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
  • Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis
  • Has provided tumor tissue sample for microsatellite instability (MSI) biomarker analysis
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to the start of study intervention
  • Has adequate organ function as demonstrated by laboratory testing within 10 days prior to the start of study treatment

Exclusion Criteria

  • Has squamous cell or undifferentiated gastric cancer
  • Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, anticipation of the need for major surgery during the course of study intervention, or has not recovered adequately from the toxicity and/or complications from previous surgery
  • Has preexisting peripheral neuropathy >Grade 1
  • Is a WOCBP who has a positive urine pregnancy test within 24 hours for urine or within 72 hours for serum prior to randomization or treatment allocation
  • Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant and/or adjuvant therapy as long as it was completed ≥6 months prior to randomization
  • Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1 or anti-programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX- 40, CD137)
  • Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization or has not recovered from all adverse events (AEs) due to any previous therapies to ≤Grade 1 or baseline
  • Has received prior radiotherapy within 2 weeks prior to study start or has not recovered from all previous radiation-related toxicities, required corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease
  • Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatment
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
  • Has known active CNS metastases and/or carcinomatous meningitis
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a known history of human immunodeficiency virus (HIV) infection
  • Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as Hepatitis C virus [HCV] ribonucleic acid [RNA] detected qualitatively) infection
  • Has a known history of active tuberculosis
  • Has hypokalemia (serum potassium less than the lower limit of normal)
  • Has hypomagnesemia (serum magnesium less than the lower limit of normal)
  • Has hypocalcemia (serum calcium less than the lower limit of normal)
  • Has a history or current evidence of any condition (eg, known deficiency of the enzyme dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is last
  • Has had an allogenic tissue/solid organ transplant
  • Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents (including, but not limited to, infusional 5-fluorouracil or oral capecitabine) and/or to any of their excipients
  • For participants taking cisplatin: has Grade ≥2 audiometric hearing loss
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): NCT03675737


Locations
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Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
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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] September 28, 2022

More Information
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Additional Information:

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

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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT03675737    
Other Study ID Numbers: 3475-859
MK-3475-859 ( Other Identifier: Merck )
KEYNOTE-859 ( Other Identifier: Merck )
JAPIC-CTI ( Registry Identifier: 194649 )
2018-001757-27 ( EudraCT Number )
First Posted: September 18, 2018    Key Record Dates
Results First Posted: October 12, 2023
Last Update Posted: October 12, 2023
Last Verified: September 2023
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 LLC:
programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
programmed cell death ligand 2 (PD-L2, PDL2)
Additional relevant MeSH terms:
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Adenocarcinoma
Stomach Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Pembrolizumab
 Fluorouracil
Capecitabine
Oxaliplatin
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs