This clinical trial is to evaluate the efficacy and safety of subjects with metastatic gastric adenocarcinoma or adenocarcinoma of the gastroesophageal junction. In addition, this clinical trial is performed to analyze the genome-specific response rate and genome analysis to identify predictive markers that respond to investigational drug administration.

Treatment

4 weeks (28 days) administration is considered as 1 cycle.
[Vactosertib, TEW-7197)]
A 300mg dose is administered orally as tablets twice a day for 5 days, followed by a 2 day holiday.
 (5 days medication/2 days off).
 All doses are taken in the morning/evening, approximately 12 hours apart, regardless of food.
[Ramucirumab (ramucirumab)]
A dose of 8 mg/kg (8 mg per kg of body weight) is administered once for 60 minutes at the 1st and 15th days of each cycle.
 This drug is administered directly into a blood vessel using an infusion pump.
[paclitaxel (paclitaxel)]
A dose of 80mg/m2 is administered intravenously for 60 minutes at the 1st, 8th, 15th day of each cycle, with a one-week break

Arm Label

Target Number of Participant

Arm Type

Arm Description

4 weeks (28 days) administration is considered as 1 cycle.
[Vactosertib, TEW-7197)]
A 300mg dose is administered orally as tablets twice a day for 5 days, followed by a 2 day holiday.
 (5 days medication/2 days off).
 All doses are taken in the morning/evening, approximately 12 hours apart, regardless of food.
[Ramucirumab (ramucirumab)]
A dose of 8 mg/kg (8 mg per kg of body weight) is administered once for 60 minutes at the 1st and 15th days of each cycle.
 This drug is administered directly into a blood vessel using an infusion pump.
[paclitaxel (paclitaxel)]
A dose of 80mg/m2 is administered intravenously for 60 minutes at the 1st, 8th, 15th day of each cycle, with a one-week break

Gender

Age

Description

1.Patients with histologically or cytologically confirmed gastric cancer, including gastric adenocarcinoma or GEJ adenocarcinoma.
2.Patients with metastatic or locally recurrent unresectable disease.
3.Patients with diseased lesions that can be measured using standard computed tomography (CT) or magnetic resonance imaging (MRI).
4.Patients who have experienced disease progression during or after primary therapy for metastatic disease.
5.Patients over 19 years of age.
6.All clinically significant toxic effects of previous chemotherapy, surgery, radiation therapy, or hormone therapy are rated ≤1 (or neuropathic Cases ≤2 grade) (excluding hair loss).
7.Patients with an Eastern Oncology Cooperative Group Performance Status (ECOG PS) score of 0 or 1.
8.Total bilirubin ≤1.5 mg/dL (25.65 µmol/L), and aspartic acid aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN; or 5.0 x with liver metastasis) Patients with adequate liver function as defined by ULN).
9. Patients without the following conditions:
• Child-Pugh B (or C) level of cirrhosis or
• A history of cirrhosis (random grade) and hepatic encephalopathy or clinically significant ascites due to cirrhosis. Clinically significant ascites are defined as ascites resulting from cirrhosis and requiring diuretics or puncture.
10. Serum creatinine ≤1.5 x ULN or creatinine clearance (measured through 24-hour urine collection) ≥40 mL/minute (i.e., if serum creatinine is >1.5 x ULN, a 24-hour urine collection is performed to calculate the creatinine clearance rate) Patients with adequate renal function as defined by
11.Patients with a urine protein of ≤1+ on dipstick or routine urinalysis (UA) (if urine dipstick or routine analysis shows ≥2+ urine protein, 24 hours for protein to allow participation in this clinical trial) Urine collection should confirm that the protein is <1000 mg within 24 hours).
12. Patients with adequate blood function with an absolute neutrophil count (ANC) ≥1500/µL, hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets ≥100,000/µL.

13.	환자는 국제 정상화 비율 (INR) ≤1.5 및 부분 트롬보플라스틴 시간 (PTT)이 ULN의 5초 이내 (항응고 요법을 받지 않는 경우)로 정의한 적절한 응고 기능을 나타내야 한다. 최대-용량 항응고 요법을 투여 중인 환자는 반드시 경구 항응고제 또는 저분자량 헤파린의 안정 용량 (적어도 14일 동안)을 투여 중이어야 한다. 와파린을 투여 받고 있다면, 환자는 INR ≤3.0이고 활성 출혈이 없거나 (즉, 임상시험계획서 요법의 최초 투여 전 14일 이내에 출혈이 없음) 또는 출혈 위험이 높은 병리적 상태 (예: 대혈관을 침범한 종양 또는 알려진 정맥류)가 없어야 한다. 절제되지 않은 원발성 종양 또는 절제 후에 재발한 국소 종양이 있으면서 항응고 요법을 투여 중인 환자는 적합하지 않다.
14.	환자가 일차 요법의 일부로서 이전에 anthracycline 요법을 투여 받은 경우, 유의한 피로 또는 호흡곤란 없이 일상적인 신체 활동에 참여할 수 있어야 한다 (뉴욕심장협회 I등급 기능과 동등) (49).
15.	성생활을 하는 환자는 반드시 폐경 후이거나 수술적으로 불임이거나, 또는 효과적인 피임법 (호르몬 또는 차단식)을 사용 중이어야 한다.
16.	가임기 여성 환자는 등록 전 7일 이내에 반드시 혈청 임신 검사 음성이어야 한다.
17.	서면 시험대상자 동의서를 제공할 수 있는 환자.
18.	생검 가능한 부위가 있는 환자.

1.Patients previously receiving treatment targeting the TGF-β signaling pathway
2.Patients who previously received Taxane-based chemotherapy
3.Patients with recorded and/or symptomatic brain or meningeal metastases.
4.Patients who experienced Grade 3-4 GI bleeding within 3 months prior to enrollment.
5.Patients who have experienced arterial thromboembolic events including, but not limited to, myocardial infarction, transient ischemic attack, cerebrovascular attack, or unstable angina within 6 months prior to enrollment.
6.Ongoing or active infection, symptomatic congestive heart failure, unstable angina, symptomatic or poorly controlled cardiac arrhythmias, uncontrolled thrombotic or hemorrhagic disease, interstitial pneumonia or pulmonary fibrosis, or in the judgment of the treating physician. Patients with other serious medical conditions that are not controlled.
7.Patients with ongoing or active psychiatric conditions or social situations that may limit adherence to treatment.
8.Patients with uncontrolled or poorly controlled hypertension (systolic >160 mmHg or diastolic >100 mmHg for >4 weeks) despite standard medical care.
9. Patients with serious or non-healing wounds, wound healing complications, ulcers, gastrointestinal perforations or fractures within 28 days prior to enrollment.
10. Patients who received chemotherapy, radiation therapy, immunotherapy or targeted therapy for gastric cancer within 2 weeks prior to enrollment
11. Patients who received other investigational drugs within 30 days prior to enrollment
12. Patients who have undergone major surgery within 28 days prior to enrollment or who have implanted subcutaneous vein access devices within 7 days prior to enrollment.
13. Patients previously receiving therapy with VEGF (including bevacizumab) or agents that directly inhibit VEGF receptor 2 activity, or with anti-angiogenic agents.
14. Patients on chronic antiplatelet therapy including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs; ibuprofen, naproxen and others), dipyridamole or clopidogrel or similar agents. Once daily aspirin use (maximum dose 325 mg/day) is permitted.
15. Patients requiring pending or scheduled surgery during the course of the clinical trial.
16. Patients with a known history of hypersensitivity reactions or suspected of hypersensitivity reactions to the active ingredients and excipients of investigational drugs or concomitant drugs
17. Pregnant or breastfeeding patients.
18. Patients known to be positive for human immunodeficiency virus (HIV) infection.
19. Patients with known alcohol or drug dependence.
20. Patients with active malignancies in addition to appropriately treated non-melanoma skin cancer, other non-invasive carcinoma or intraepithelial cancer.
21. Patients unable to take oral medication
22. Patients should not have received more than one line of prior therapy in a metastatic situation.

According to RECIST 1.1, response rate of the combination of vactosertib(TEW-7197) and ramucirumab/paclitaxel

every6weeks

Safety

every3weeks