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)

Gastric Cancer Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03382600
• Other study ID #: 3475-659
• Secondary ID: MK-3475-659KEYNO
• Status: Completed
• Phase: Phase 2
• Start date: March 26, 2018
• Est. completion date: May 30, 2021

Study information

• Verified date: May 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: May 30, 2021
• Est. primary completion date: May 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Gastric Cancer
• Stomach Neoplasms

Intervention

Biological:
• Pembrolizumab
200 mg Q3W on Day 1 by IV infusion

Drug:
• Oxaliplatin
130 mg/m^2 Q3W on Day 1 by IV infusion
• TS-1
40 to 60 mg orally according to Body Surface Area (BSA) BID Q3W on Days 1-14
• Cisplatin
60 mg/m^2 Q3W on Day 1 by IV infusion

Locations

Country	Name	City	State
Japan	Hyogo Cancer Center ( Site 0016)	Akashi	Hyogo
Japan	Chiba Cancer Center ( Site 0012)	Chiba
Japan	Kyushu University Hospital ( Site 0014)	Fukuoka
Japan	National Hospital Organization Kyushu Cancer Center ( Site 0017)	Fukuoka
Japan	Gifu University Hospital ( Site 0021)	Gifu
Japan	Ibaraki Prefectural Central Hospital ( Site 0018)	Kasama	Ibaraki
Japan	National Cancer Center Hospital East ( Site 0001)	Kashiwa	Chiba
Japan	Saitama Cancer Center ( Site 0004)	Kitaadachi-gun	Saitama
Japan	Kobe City Medical Center General Hospital ( Site 0015)	Kobe	Hyogo
Japan	Kochi Health Sciences Center ( Site 0022)	Kochi
Japan	Kumamoto University Hospital ( Site 0002)	Kumamoto
Japan	National Hospital Organization Shikoku Cancer Center ( Site 0024)	Matsuyama	Ehime
Japan	Gunma Prefectural Cancer Center ( Site 0005)	Ohta	Gunma
Japan	Osaka International Cancer Institute ( Site 0011)	Osaka
Japan	Kindai University Hospital ( Site 0013)	Osakasayama	Osaka
Japan	Kitasato University Hospital ( Site 0019)	Sagamihara	Kanagawa
Japan	Hokkaido University Hospital ( Site 0006)	Sapporo	Hokkaido
Japan	Tohoku University Hospital ( Site 0023)	Sendai	Miyagi
Japan	Jichi Medical University Hospital ( Site 0009)	Shimotsuke	Tochigi
Japan	Osaka University Hospital ( Site 0010)	Suita	Osaka
Japan	Shizuoka Cancer Center Hospital and Research Institute ( Site 0020)	Sunto-gun	Shizuoka
Japan	National Cancer Center Hospital ( Site 0025)	Tokyo
Japan	The Cancer Institute Hospital of JFCR ( Site 0007)	Tokyo
Japan	Tokyo Metropolitan Komagome Hospital ( Site 0008)	Tokyo
Japan	Kanagawa Cancer Center ( Site 0003)	Yokohama	Kanagawa

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Country where clinical trial is conducted

Japan, 

References & Publications (1)

https://pubmed.ncbi.nlm.nih.gov/35701865/

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Merck Oncology Clinical Trials Information