Clinical Trials /

Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With TS-1+Cisplatin or TS-1+Oxaliplatin as First Line Chemotherapy in Gastric Cancer (MK-3475-659/KEYNOTE-659)

NCT03382600

Description:

The purpose of this study is to estimate overall response rates (ORRs) of pembrolizumab + oxaliplatin + TS-1 and pembrolizumab + cisplatin + TS-1, as first-line treatment for gastric cancer in programmed death-ligand 1 (PD-L1) positive, human epidermal growth factor receptor 2 (HER2/neu)-negative participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

    <li>Brief Title: Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With TS-1+Cisplatin or TS-1+Oxaliplatin as First Line Chemotherapy in Gastric Cancer (MK-3475-659/KEYNOTE-659)li><li>Official Title: A Phase IIb, Clinical Trial to Study the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With TS-1+Cisplatin or TS-1+Oxaliplatin as a First Line Chemotherapy in Participants With Advanced or Recurrent Gastric Cancer (KEYNOTE-659)li>

Clinical Trial IDs

    <li>ORG STUDY ID: 3475-659li><li>NCT ID: NCT03382600li>

Conditions

    <li>Gastric Cancerli>

Interventions

<td>Pembrolizumabtd><td>MK-3475td><td>Pembrolizumab + Oxaliplatin +TS-1 (Cohort 1)td><td>Oxaliplatintd><td/><td>Pembrolizumab + Oxaliplatin +TS-1 (Cohort 1)td><td>TS-1td><td/><td>Pembrolizumab + Oxaliplatin +TS-1 (Cohort 1)td><td>Cisplatintd><td/><td>Pembrolizumab + Cisplatin +TS-1 (Cohort 2)td>
DrugSynonymsArms

Purpose

The purpose of this study is to estimate overall response rates (ORRs) of pembrolizumab + oxaliplatin + TS-1 and pembrolizumab + cisplatin + TS-1, as first-line treatment for gastric cancer in programmed death-ligand 1 (PD-L1) positive, human epidermal growth factor receptor 2 (HER2/neu)-negative participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Detailed Description

      Approximately 45 participants will be assigned first to pembrolizumab + oxaliplatin + TS-1
      combination therapy (Cohort 1), and then 45 participants will be assigned to pembrolizumab +
      cisplatin + TS-1 combination therapy (Cohort 2).
    

Trial Arms

<td>Pembrolizumab + Oxaliplatin +TS-1 (Cohort 1)td><td>Experimentaltd><td>Participants receive Pembrolizumab 200 mg every 3 weeks (Q3W) plus oxaliplatin 130 mg/m^2 Q3W by intravenous (IV) infusion plus TS-1 twice daily (BID) by continuous oral administration for 14 days, followed by a recovery period of 7 days. Study treatment will be started on Day 1 of each 3-week course.td><td>
    <li>Oxaliplatinli><li>TS-1li>
td><td>Pembrolizumab + Cisplatin +TS-1 (Cohort 2)td><td>Experimentaltd><td>Participants receive Pembrolizumab 200 mg Q3W plus cisplatin 60 mg/m^2 Q3W by IV infusion plus TS-1 BID by continuous oral administration for 14 days, followed by a recovery period of 7 days. Study treatment will be started on Day 1 of each 3-week course.td><td>
    <li>TS-1li><li>Cisplatinli>
td>
NameTypeDescriptionInterventions

Eligibility Criteria

        Inclusion Criteria:

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Has histologically- or cytologically-confirmed diagnosis of locally advanced
             unresectable or metastatic gastric or GEJ adenocarcinoma

          -  Has a PD-L1 positive tumor as determined by immunohistochemistry (IHC) at a central
             laboratory

          -  Has measurable disease as defined by RECIST 1.1 as determined by investigator
             assessment. Tumor lesions situated in a previously irradiated area are considered
             measurable if progression has been demonstrated in such lesions

          -  Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy
             test at the timing of enrollment

          -  Participants of childbearing potential must be willing to use an adequate method of
             contraception for the course of the study through 120 days after the last dose of
             study medication

          -  Has adequate organ function

        Exclusion Criteria:

          -  Has squamous cell or undifferentiated gastric cancer

          -  HER2-positive status

          -  Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ
             cancer

          -  A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation

          -  Has received prior therapy with a platinum-based anti-cancer drug

          -  Has had major surgery, open biopsy or significant traumatic injury within 28 days
             prior to enrollment, or anticipation of the need for major surgery during the course
             of study treatment

          -  Has had radiotherapy within 14 days of enrollment

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 5 years

          -  Has clinically active central nervous system (CNS) metastases and/or carcinomatous
             meningitis

          -  Has an active autoimmune disease that has required systemic treatment in the past 2
             years with use of disease modifying agents, corticosteroids, or immunosuppressive
             drugs

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has any active infection requiring systemic therapy

          -  Will be on flucytosine at the time of enrollment

          -  Has grade ≥ 2 peripheral sensory neuropathy

          -  Has poorly controlled diarrhea (e.g., watery stool, uncontrollable bowel movement with
             drugs, grade ≥ 2 and number of defecations, ≥ 5/day)

          -  Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage within 2
             weeks prior to enrollment

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with participation for the
             full duration of the trial, or is not in the best interest of the participant, in the
             opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of study treatment

          -  Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or anti
             PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell
             receptor

          -  Has known history of human immunodeficiency virus (HIV) [HIV1/2 antibodies]

          -  Has a known history of Hepatitis B

          -  Has received live vaccine within 30 days of the planned start of study therapy

          -  Is currently participating in and receiving study therapy or has participated in a
             study of an investigational agent and received study therapy or used an
             investigational device within 4 weeks prior to the first dose of trial treatment
      
<td>Maximum Eligible Age:td><td>75 Yearstd><td>Minimum Eligible Age:td><td>18 Yearstd><td>Eligible Gender:td><td>Alltd><td>Healthy Volunteers:td><td>Notd>

Primary Outcome Measures

<td>Measure:td><td>Objective response rate (ORR) according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) assessed by Blinded Independent Central Review (BICR)td><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>For the primary efficacy analysis, ORR is defined as the percentage of participants who have a best response of Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 as assessed by BICR.td>

Secondary Outcome Measures

<td>Measure:td><td>ORR according to immune-related Response Evaluation Criteria In Solid Tumors (iRECIST) assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>For the secondary efficacy analysis, ORR is defined as the percentage of participants whose best response based on imaging is CR (disappearance of all lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters) according to iRECIST as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression. At initial Progressive Disease (PD) by RECIST 1.1, if participant is clinically stable the investigator may continue to treat and scan again 4-8 weeks later to see if PD confirmed by iRECIST criteria.td>
<td>Measure:td><td>Duration of Response (DOR) according to RECIST 1.1 assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>For participants who demonstrate CR or PR according to RECIST 1.1 as assessed by BICR, DOR is defined as the time from the earliest date of qualifying response (CR or PR) until earliest date of disease progression or death from any cause, whichever comes first. DOR will be censored at the last tumor assessment date if a responder does not have PD or death.td>
<td>Measure:td><td>DOR according to iRECIST assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>For participants who demonstrate CR or PR according to iRECIST as assessed by BICR, DOR is defined as the time from the earliest date of qualifying response (CR or PR) until earliest date of disease progression or death from any cause, whichever comes first. DOR will be censored at the last tumor assessment date if a responder does not have PD or death. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.td>
<td>Measure:td><td>Disease Control Rate (DCR) according to RECIST 1.1 assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>DCR is defined as the percentage of participants in the analysis population who have CR (disappearance of all lesions), PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD). Responses are according to RECIST 1.1 as assessed by BICR.td>
<td>Measure:td><td>DCR according to iRECIST 1.1 assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>DCR is defined as the percentage of participants in the analysis population who have CR (disappearance of all lesions), PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD). Responses are according to iRECIST 1.1 as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.td>
<td>Measure:td><td>Time to Response (TTR) according to RECIST 1.1 assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>TTR is defined as the time from the date of enrollment day to the first date of confirmed CR (disappearance of all lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters). Responses are according to RECIST 1.1 as assessed by BICR.td>
<td>Measure:td><td>TTR according to iRECIST 1.1 assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>TTR is defined as the time from the date of enrollment day to the first date of confirmed CR (disappearance of all lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters). Responses are according to iRECIST 1.1 as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.td>
<td>Measure:td><td>Progression-free Survival (PFS) according to RECIST 1.1 assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>PFS is defined as the time from the date of enrollment day to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by BICR.td>
<td>Measure:td><td>PFS according to iRECIST 1.1 assessed by BICRtd><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>PFS is defined as the time from the date of enrollment day to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to iRECIST 1.1 as assessed by BICR. iRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression.td>
<td>Measure:td><td>Overall survival (OS)td><td>Time Frame:td><td>Up to ~2 yearstd><td>Safety Issue:td><td/><td>Description:td><td>OS is defined as the time from the date of enrollment day to death due to any cause. Participants without documented death at the time of the final analysis will be censored at the date of the last follow-up.td>
<td>Measure:td><td>Adverse events (AEs)td><td>Time Frame:td><td>From time of allocation up to 30 days following cessation of study treatment (up to ~2 years)td><td>Safety Issue:td><td/><td>Description:td><td>The number of participants that experience an AE will be reported for each arm. An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatmenttd>
<td>Measure:td><td>Treatment discontinuations due to AEstd><td>Time Frame:td><td>From time of allocation up to 30 days following cessation of study treatment (up to ~2 years)td><td>Safety Issue:td><td/><td>Description:td><td>The number of participants that discontinue study drug due to an AE will be reported for each arm. An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.td>

Details

<td>Phase:td><td>Phase 2td><td>Primary Purpose:td><td>Interventionaltd><td>Overall Status:td><td>Recruitingtd><td>Lead Sponsor:td><td>Merck Sharp &amp; Dohme Corp.td>

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