An Open Label Phase 2 Study to Evaluate the Safety and Efficacy of Lenvatinib With Pembrolizumab or Lenvatinib, Pembrolizumab and FLOT in the Neoadjuvant / Adjuvant Treatment for Patients With Gastric Cancer

An Open Label Phase 2 Study to Evaluate the Safety and Efficacy of Lenvatinib With Pembrolizumab or Lenvatinib, Pembrolizumab and FLOT in the Neoadjuvant / Adjuvant Treatment for Patients With Gastric Cancer

This study is an open label phase 2 study to evaluate the safety and efficacy of Lenvatinib with Pembrolizumab or Lenvatinib, Pembrolizumab and FLOT in the neoadjuvant / adjuvant treatment for Patients with Gastric Cancer.

This study is an open-label, single-arm, single-center, phase 2 clinical trial. Eligible patients are with previously untreated gastric and gastroesophageal junction adenocarcinoma as defined by cT2-4 and/or cN+ without evidence of metastatic disease. Patients in the exploratory cohort will receive 3 cycles of 20 mg oral Lenvatinib daily plus 200 mg intravenous Pembrolizumab every 3 weeks as the neoadjuvant treatment followed by surgery, and then 3 cycles of Lenvatinib plus Pembrolizumab followed by 11 cycles of Pembrolizumab monotherapy as the adjuvant treatment. Also, Patients in the FLOT cohort will receive 3 cycles of 8 mg oral Lenvatinib daily, 200 mg intravenous Pembrolizumab every 3 weeks and FLOT (Docetaxel 50 mg/m2, Oxaloplatin 85 mg/m2, Levofolinate 200 mg/m2, 5-FU 2600 mg/m2) every 2 weeks as the neoadjuvant treatment followed by surgery, and then 3 cycles of Lenvatinib ,Pembrolizumab plus FLOT followed by 11 cycles of Pembrolizumab monotherapy as the adjuvant treatment.

Inclusion Criteria:

1. Have gastric and gastroesophageal junction adenocarcinoma

2. Untreated and cT2-4 and/or cN+ without evidence of metastatic disease

3. Patients at least 20 years of age on the day of providing consent.

4. Patients with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group.

5. Patients with adequate organ function at the time of enrollment as defined below:

   • Neutrophil count ≥1500mm3
   • Platelet count ≥10 × 100,000/mm3
   • Hemoglobin (Hb) ≥ 9.0 g/dL,
   • Total bilirubin ≤1.5 mg/dL
   • AST (GOT) and ALT (GPT) ≤ 100 IU/L
   • Creatinine ≤1.5 mg/dL
   • 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
   • International normalized ratio (INR) ≤ 1.5

6. Patients who not received a blood transfusion within 14 days of registration.

7. Patients have recovered adverse events associated with radiation and surgical operation as pretreatment to Grade 1 or less or baseline or less with CTCAE v5.0 excluding stable symptoms. However, adverse events with stable symptoms even with Grade 2 or higher excluded.

8. 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 or use of a male condom plus partner use of contraceptive method [an intrauterine device or hormone releasing system, a 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.

9. Patients capable of taking oral medication.

10. Patients who provided written informed consent to be subjects in this study.

Exclusion Criteria:

1. Patients who have undergone surgical treatment and radiotherapy within 2 weeks before enrollment.
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.
3. 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.
4. Patients with a history of New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction.
5. Patients have an addigional 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.
6. Patients have severe (hospitalization required) complications (intenstinal palsy, intestinal obstruction, pulmonary fibrosis, diabetes difficult to control, heart failure, myocardial infarction, unstable angina, renal failure, liver failure, mental disease, cerebrovascular disease etc).
7. Patients with a history of a gastrointestinal perforation and /or gastrointestinal fistula within 6 months before enrollment.
8. Is infected with active hepatitis B (defined as HBs antigen positive) or hepatitis C.
9. Patients with a history of human immunodeficiency virus (HIV).
10. Patients with a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
11. Patients who are administered live vaccines <30 days before the initiation of treatment with the investigational drug.
12. Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease.
13. 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.
14. Patients have serious non-healing wound, ulcer, or bone fracture.
15. Females who are pregnant or breastfeeding.
16. Patients have no intention to comply with the protocol or cannot comply.
17. Patients were judged unsuitable as subject of this study by investigator.