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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)

Phase IIb study of Pembrolizumab in combination with TS-1+Cisplatin or TS-1+Oxaliplatin in GC

100

A total of 100 patients were enrolled. 54 of them were enrolled in Pembrolizumab + Oxaliplatin + TS-1 (Cohort 1) and 46 patients were enrolled in Pembrolizumab + Cisplatin +TS-1 (Cohort 2). The mean age of the population was 62.1 years (61.5 years in Cohort 1, 62.9 years in Cohort 2), and approximately 70% of the patients were male (79.6% in Cohort 1, 60.9% in Cohort 2).

Enrolled: 100 (Cohort 1:54, Cohort 2:46) Treated: 100 (Cohort 1:54, Cohort 2:46) Completed: 0 (Cohort 1:0, Cohort 2:0) Reasons for treatment discontinuation: - Adverse events: 6 (Cohort 1: 3, Cohort 2:3) - Clinical disease progression: 6 (Cohort 1:2, Cohort 2:4) - Radiological progression: 71 (Cohort 1:40, Cohort 2:31) - Withdrawal by patient: 1(Cohort 1:0, Cohort 2:1) - Other: 16 (Cohort 1:9, Cohort 2:7)

Analysis Population: All Subjects as Treated (all patients who received at least one dose of study drug) 100 patients (Breakdown is 54 patients in Cohort 1 and 46 patients in Cohort 2) All patients experienced Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs). Serious TEAEs and serious TRAEs were reported in 49 patients (27 patients in Cohort 1 and 22 patients in Cohort 2) and 35 patients (18 patients in Cohort 1 and 17 patients in Cohort 2) respectively. Most common (Expression ratio 30% or more) TEAEs: - In Cohort 1 peripheral sensory neuropathy (94.4%), decreased appetite (70.4%), nausea (63.0%), platelet count decreased (53.7%), constipation (44.4%), diarrhoea (44.4%), neutrophil count decreased (44.4%), malaise (40.7%), and dysgeusia (35.2%) - In Cohort 2 neutrophil count decreased (69.6%), decreased appetite (67.4%), constipation (65.2%), nausea (60.9%), diarrhoea (47.8%), anaemia (39.1%), stomatitis (37.0%), fatigue (32.6%), malaise (32.6%), dysgeusia (32.6%), and peripheral sensory neuropathy (30.4%) Serious TEAEs: Deaths Due to Adverse Events: 3 patients (Cohort 1) Most common (Expression ratio 5% or more) SAEs: - In Cohort 1 adrenal insufficiency (5.6%) - In Cohort 2 adrenal insufficiency and pneumonia (6.5% each)

Analysis Ppopulation: All Subjects as Treated 100 patients 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): The ORR was 72.2% (95% CI: 58.4 - 83.5) in Cohort 1 and 80.4% (95% CI: 66.1 - 90.6) in Cohort 2

Analysis Ppopulation: All Subjects as Treated 100 patients *The analyzed population for duration of response (DOR) consists of 76 patients with the best response of complete response (CR) or partial response (PR) in the All Subjects as Treated (39 patients in Cohort 1 and 37 patients in Cohort 2) - ORR According to Immune-related Response Evaluation Criteria In Solid Tumors (iRECIST) Assessed by BICR: The ORR was 72.2% (95% CI: 58.4 - 83.5) in Cohort 1 and 80.4% (95% CI: 66.1 - 90.6) in Cohort 2. - DOR According to RECIST 1.1 Assessed by BICR: The mediam DOR was 10.6 months (95% CI: 5.6 - NA) in Cohort 1 and 9.5 months (95% CI: 4.7 - 15.3) in Cohort 2. - DOR According to iRECIST Assessed by BICR: The mediam DOR was 10.6 months (95% CI: 5.6 - NA) in Cohort 1 and 9.5 months (95% CI: 4.7 - NA) in Cohort 2. - Disease Control Rate (DCR) According to RECIST 1.1 and iRECIST Assessed by BICR: The DCR was 96.3% (95% CI: 87.3 - 99.5) in Cohort 1 and 97.8% (95% CI: 88.5 - 99.9) in Cohort 2. - Time to Response (TTR) According to RECIST 1.1 and iRECIST Assessed by BICR: The mediam TTR was 1.5 months in both Cohorts. - Progression-free Survival (PFS) According to RECIST 1.1 Assessed by BICR: The mediam PFS was 9.4 months (95% CI: 6.6 - 12.6) in Cohort 1 and 8.3 months (95% CI: 5.8 - 15.3) in Cohort 2. - PFS According to iRECIST 1.1 Assessed by BICR: The mediam PFS was 9.4 months (95% CI: 6.6 - 12.6) in Cohort 1 and 10.9 months (95% CI: 6.7 - NA) in Cohort 2. - Overall Survival (OS): The mediam OS was 16.9 months (95% CI: 13.4 - 20.0) in Cohort 1 and 17.1 months (95% CI: 12.6 - 23.1) in Cohort 2. Safety The incidence of adverse events is described in the Adverse events section.

The combination of pembrolizumab with Oxaliplatin +TS-1 or Cisplatin +TS-1 demonstrated promising efficacy and manageable safety in Japanese patients with PD-L1-positive, HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma.

Mar. 04, 2020

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

Yes

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf http://engagezone.msd.com/ds_documentation.php

Taiho Pharmaceutical Co., Ltd.

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toiawaseCD1@taiho.co.jp

Taiho Pharmaceutical Co., Ltd.

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+81-3-3293-2113

toiawase@taiho.co.jp

completed

April. 20, 2018

Interventional

Unblinded Open-label

treatment purpose

2

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale at the timing of enrollment.
- Have histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.
- Have a PD-L1 positive tumor as determined by IHC at a central laboratory.
- Have 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.
- Female subjects 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.
- Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
- Demonstrate adequate organ function.

- Has squamous cell or undifferentiated gastric cancer.
- Participants with human epidermal growth factor receptor 2 (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. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- 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.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Has an active autoimmune disease that has required systemic treatment in past 2 years.
- 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 current pneumonitis.
- Has an active infection requiring systemic therapy.
- Being on flucytosine at the time of enrollment.
- Has grade 2 or more peripheral sensory neuropathy.
- Has poorly controlled diarrhea (e.g., watery stool, uncontrollable bowel movement with drugs, grade 2 or more and number of defecations, 5 or more/day).
- Accumulation of pleural, ascitic, or pericardial fluid requiring drainage within 2 weeks prior to enrollment.
- Has a history or current evidence of any condition (e.g. known deficiency of the enzyme dihydropyrimidine dehydrogenase [DPD]), therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, 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-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 a known history of Human Immunodeficiency Virus (HIV).
- Has a known history of Hepatitis B or known active Hepatitis C virus infection.
- 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.
- Has received a live vaccine within 30 days of planned start of study therapy.

Both

Gastric Adenocarcinoma

investigational material(s)
Generic name etc : Pembrolizumab + oxaliplatin + TS-1 (tegafur + gimeracil + oteracil potassium)
INN of investigational material : pembrolizumab, oxaliplatin, TS-1:tegafur, gimeracil, oteracil potassium
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Cohort 1: Pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W) + oxaliplatin 130 mg/m2 IVinfusion Q3W + TS-1 continuous oral administration twice daily (BID) for 14 days followed by a recovery period of 7 days
Generic name etc : Pembrolizumab + cisplatin + TS-1 (tegafur + gimeracil + oteracil potassium)
INN of investigational material : pembrolizumab, cisplatin, TS-1:tegafur, gimeracil, oteracil potassium
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Cohort 2: Pembrolizumab 200 mg fixed dose administered Q3W + cisplatin 60 mg/m2 IV infusion Q3W + TS-1 continuous oral administration BID for 14 days followed by a recovery period of 7 days

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

efficacy
Overall Response Rate (ORR)
To evaluate Overall Response Rate (ORR) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR).

efficacy
Duration of Response (DOR)
To evaluate the Duration of Response (DOR) per RECIST 1.1 and per iRECIST as assessed by BICR.

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Mar. 20, 2018