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)

Study Overview
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Brief Summary
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The purpose of this study is to estimate objective 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
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Approximately 45 participants will be assigned to pembrolizumab + oxaliplatin + TS-1 combination therapy (Cohort 1) first, and then 45 participants will be assigned to pembrolizumab + cisplatin + TS-1 combination therapy (Cohort 2).

Official Title
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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)

Conditions
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Gastric Cancer

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Oxaliplatin
* Drug: TS-1
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Oxaliplatin +TS-1 (Cohort 1)<br>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, and will continue for up to  3 years. | Biological: Pembrolizumab<br>* 200 mg Q3W on Day 1 by IV infusion<br>* Other names: MK-3475;Drug: Oxaliplatin<br>* 130 mg/m^2 Q3W on Day 1 by IV infusion<br>Drug: TS-1<br>* 40 to 60 mg orally according to Body Surface Area (BSA) BID Q3W on Days 1-14<br>|
| Experimental: Pembrolizumab + Cisplatin +TS-1 (Cohort 2)<br>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, and will continue for up to  3 years. | Biological: Pembrolizumab<br>* 200 mg Q3W on Day 1 by IV infusion<br>* Other names: MK-3475;Drug: TS-1<br>* 40 to 60 mg orally according to Body Surface Area (BSA) BID Q3W on Days 1-14<br>Drug: Cisplatin<br>* 60 mg/m^2 Q3W on Day 1 by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | For the primary efficacy analysis, ORR was 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 SOD) per RECIST 1.1 as assessed by BICR. | Up to  36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR According to Immune-related Response Evaluation Criteria In Solid Tumors (iRECIST) Assessed by BICR | For the secondary efficacy analysis, ORR was defined as the percentage of participants whose best response based on imaging is CR (disappearance of all target lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD) 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. | Up to  36 months | 
| Duration of Response (DOR) According to RECIST 1.1 Assessed by BICR | For participants who demonstrated complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the SOD of target lesions) according to RECIST 1.1 as assessed by BICR, DOR was defined as the time from the earliest date of qualifying response (CR or PR) until earliest date of progressive disease (PD, ≥20% increase in the SOD of target lesions) or death from any cause, whichever came first. DOR was censored at the last tumor assessment date if a responder did not have PD or death. | Up to  36 months | 
| DOR According to iRECIST Assessed by BICR | For participants who demonstrated complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the SOD of target lesions) according to iRECIST as assessed by BICR, DOR was defined as the time from the earliest date of qualifying response (CR or PR) until earliest date of progressive disease (PD, ≥20% increase in the SOD of target lesions) or death from any cause, whichever came first. DOR was censored at the last tumor assessment date if a responder did 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. | Up to  36 months | 
| Disease Control Rate (DCR) According to RECIST 1.1 Assessed by BICR | DCR was defined as the percentage of participants in the analysis population who have complete response (CR, disappearance of all target lesions), partial response (PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD), or stable disease (SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD, ≥20% increase in the SOD of target lesions]). Responses are according to RECIST 1.1 as assessed by BICR. | Up to  36 months | 
| DCR According to iRECIST 1.1 Assessed by BICR | DCR was defined as the percentage of participants in the analysis population who have CR (disappearance of all target lesions), PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD), or stable disease (SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD [≥20% increase in the SOD of target lesions]). 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. | Up to  36 months | 
| Time to Response (TTR) According to RECIST 1.1 Assessed by BICR | TTR was defined as the time from the date of enrollment day to the first date of confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD). Responses are according to RECIST 1.1 as assessed by BICR. | Up to  36 months | 
| TTR According to iRECIST 1.1 Assessed by BICR | TTR was defined as the time from the date of enrollment day to the first date of confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in the SOD of target lesions, taking as reference the baseline SOD). 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. | Up to  36 months | 
| Progression-free Survival (PFS) According to RECIST 1.1 Assessed by BICR | PFS was defined as the time from the date of enrollment day to the first documented PD (defined as ≥20% increase in the SOD of target lesions) or death due to any cause, whichever occurred first. Responses are according to RECIST 1.1 as assessed by BICR. | Up to  36 months | 
| PFS According to iRECIST 1.1 Assessed by BICR | PFS was defined as the time from the date of enrollment day to the first documented PD (defined as ≥20% increase in the SOD of target lesions) or death due to any cause, whichever occurred 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. | Up to  36 months | 
| Overall Survival (OS) | OS was 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 were censored at the date of the last follow-up. For these participants, date of last follow up was last visit date instead of death date. | Up to  36 months | 
| Number of Participants With ≥1 Adverse Event (AE) | 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 | Up to  36 months | 
| Number of Participants Discontinuing From Study Treatment Due to AE(s) | 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. | Up to  36 months |