Lenvatinib and Pembrolizumab Simultaneous Combination Study

In this study, if combination therapy with lenvatinib and pembrolizumab in patients with gastric cancer is judged to be effective, a prospective treatment regimen can be expected for a larger number of participating subjects.

The anticipated disadvantages include any adverse events associated with lenvatinib and pembrolizumab. To minimize the risk and disadvantages of adverse events, the data center together with the Data and Safety Monitoring Committee will monitor any adverse events in the present trial to determine whether or not they are within the expected range. These bodies will also conduct a thorough examination in the event that serious or unexpected adverse events occur, and adopt an appropriate system to take any necessary actions.

Inclusion criteria

• Patients have histologically or cytologically confirmed advanced or recurrent gastric cancer.
• Patients at least 20 years of age on the day of providing consent.
• Patients have measurable disease as defined by RECIST 1.1 as determined by investigator.
• Patients with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group.
• Patients with adequate organ function at the time of enrollment as defined below:

• Neutrophil count ≥1200mm3
• Platelet count ≥7.5 × 104/mm3
• Hemoglobin (Hb) ≥ 8.0 g/dL,
• Total bilirubin ≤1.5 mg/dL
• Asparate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 100 IU/L for subjects with liver metastases ≤ 200 IU/L
• Creatinine ≤1.5-times the upper limit of normal
• International normalized ratio (INR) ≤ 1.5
• Urinary protein : It satisfies one of the following (if any of the inspection criteria are satisfied, other examination may not be carried out) (i) Urinary protein (test paper method) is 2+ or less (ii) Urine Protein Creatinine (UPC) ratio <3.5 (iii) 24-hour urine protein was measured, urinary protein ≦ 3500 mg
• Patients who not received a blood transfusion within 7 days of registration.
• Patients have recovered adverse events associated with chemotherapy, radiation and surgical operation as pretreatment to Grade 1 or lower with CTCAE v4.0 excluding stable symptoms (eg alopecia, peripheral sensory neuropathy, skin hyperpigmentation, dysgeusia etc.).
• Female of childbearing potential who are negative in a pregnancy test within 14 days before enrollment. Both male and female patients should agree to use an adequate method of contraception (total abstinence, an intrauterine device or hormone releasing system, an contraceptive implant and an oral contraceptive) starting with the first dose of study therapy through 120 days after the last dose of study therapy. Duration will be determined when the subject is assigned to treatment.
• Patients capable of taking oral medication
• Patients who provided written informed consent to be subjects in this trial

Exclusion criteria

• Patients who received prior anticancer treatment within 14 days (or 5 times the half-life time, whichever is shorter) or any investigational agent within 28 days prior to the first dose of study drugs.
• Patients who have undergone surgical treatment and radiotherapy with in 2 weeks before enrollment.
• Patients with a history of prior treatment with Lenvatinib or any anti-programmed death 1, anti-programmed ligand death 1, or anti-programmed ligand death 2.
• Patients with hypertension that is difficult to control (systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥90 mmHg) despite treatment with several hypotensive agents.
• Patients with acute coronary syndrome (including myocardial infarction and unstable angina), and with a history of coronary angioplasty or stent placement performed within 6 months before enrollment.
• Patients with symptomatic brain metastasis.
• Patients with a history of New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months
• Patients have an active malignancy (except for definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months
• Patients have severe (hospitalization required) complications (intestinal palsy, intestinal obstruction, pulmonary fibrosis, diabetes difficult to control, heart failure, myocardial infarction, unstable angina, renal failure, liver failure, mental disease, cerebrovascular disease etc).
• Patients with a history of a gastrointestinal perforation and /or gastrointestinal fistula within 6 months before enrollment.
• Patients with active hepatitis.
• Patients with a history of human immunodeficiency virus (HIV).
• Patients with active symptoms or signs of interstitial lung disease.
• Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease
• Patients who require systemic corticosteroids (excluding temporary usage for tests, prophylactic administration for allergic reactions, or to alleviate swelling associated with radiotherapy) or immunosuppressants, or who have received such a therapy <14 days before enrollment.
• Patients have a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis
• Patients who are administered live vaccines <30 days before the initiation of treatment with the investigational drug.
• Patients have serious non-healing wound, ulcer, or bone fracture.
• Females who are pregnant or breastfeeding
• Patients have no intention to comply with the protocol or cannot comply.
• Patients were judged unsuitable as subject of this trial by investigator.