S1+ Paclitaxel (IV&IP) + Bevacizumab (IP) Versus S1+Oxaliplatin as First-line Treatment in Gastric Cancer With Malignant Ascites

S1 Plus Paclitaxel (IV&IP) Plus Bevacizumab (IP) Versus S1 Plus Oxaliplatin(IV) as First-line Treatment in Gastric or Gastroesophageal Junctional Adenocarcinoma With Malignant Ascites: An Open-label, Multicenter Phase II Study

The purpose of this study is to compare the efficacy of S1 plus paclitaxel (intravenous injection & intraperitoneal injection) plus bevacizumab (intraperitoneal injection) vs. S1 plus oxaliplatin intravenous injection as first-line treatment in gastric or gastroesophageal junctional adenocarcinoma with malignant ascites.

This is a prospective, open-label, multicenter clinical trial, to compare the efficacy of S1 plus paclitaxel (intravenous injection & intraperitoneal injection) plus bevacizumab (intraperitoneal injection) versus S1 plus oxaliplatin intravenous injection as first-line treatment in gastric or gastroesophageal junctional adenocarcinoma with malignant ascites. A total of 66 patients who are diagnosed with gastric or gastroesophageal junctional adenocarcinoma will be allocated to receive either S1 orally administration plus paclitaxel intravenous injection & intraperitoneal injection plus bevacizumab intraperitoneal injection, or to receive S1 orally administration plus oxaliplatin intravenous injection. The primary end point is ascites response rate at 6 weeks. The secondary end points include the median overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), objective response rate (ORR), puncture free survival, volume of drainage, the quality of life (QoL) and safety.

Inclusion Criteria:

• 18 years ≥ Age≤ 70 years, male or female
• Pathologically confirmed adenocarcinoma of the gastric or gastro-oesophageal junction with inoperable locally advanced or recurrent and/or metastatic disease; with medium amount of malignant ascites which can be catheterized.
• Diagnostic criteria for malignant ascites (meet any of the following criteria): ascites cytology positive; or imaging or pathological confirmed peritoneal metastases.
• No prior anti-tumor treatment to the metastatic disease; an interval of at least 6 months from the last adjuvant chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status( PS) score 0-1.
• Normal major organ function, and laboratory tests must meet the following criteria: hemoglobin (HGB) ≥ 90 g/L, neutrophil count ≥ 1.5×109/L, platelet count ≥ 100×109/L, total bilirubin (TBil) ≤ 1.5 upper normal limitation (UNL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 UNL, serum creatinine (Cr) ≤ 1 UNL; creatinine clearance rate (CCr) ≥ 60 ml/min (calculated using the Cockcroft-Gault equation).
• International Normalized Ratio (INR) ≤ 1.5 and partial prothrombin time (PPT) or activated partial thromboplastin time (APTT) ≤ 1.5 UNL within 7 days before enrollment.
• Life expectancy of at least 12 weeks
• Signed informed consent (ICF)
• For women of child bearing potential, a negative serum or urine pregnancy test result should be obtained with 7 days before enrollment; Women of childbearing potential and men must agree to use adequate contraception before entering the program until at least 8 weeks after the last study drug administration.

Exclusion Criteria:

• Known hypersensitivity or allergic to any of the study drugs, study drug classes, or excipients in the formulation.
• Subject received chemotherapy to the metastatic disease (except adjuvant/neoadjuvant chemotherapy administered 24 weeks before enrollment)
• Subject with other malignancies, except for non-melanoma skin cancer or in-situ cervical carcinoma under adequate treatment, or other treated malignancies without evidence of recurrent for 5 years.
• Anti-tumor cytotoxic drug therapy within 14 days prior to enrollment（longer washout time interval might needed depends on drug characteristics）
• Uncontrolled hypertension which cannot be reduced to normal range by antihypertensive agents [Systolic Blood Pressure(SBP) >140 mmHg, diastolic blood pressure (DBP) > 90 mmHg], coronary artery disease > grade 1, arrhythmia > grade 1 [including corrected QT(QTc) interval prolongation: QTc>450 ms for male，QTc>470 ms for female], grade 1 heart failure.
• Proteinuria ≥ ++，or persistent proteinuria > 1.0 g/24 hours
• Presence of any toxicity ≥ grade 1 according to NCI-CTCAE except for alopecia.
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks, cerebral hemorrhage、cerebral infarction), deep vein thrombosis and pulmonary embolism within 12 months before enrollment.
• Bowel obstruction within 6 weeks before enrollment.
• Surgical treatment was performed within 6 weeks before enrollment. Subject should recover from any major surgery.
• Serious uncontrolled systemic illness or medical condition or uncontrolled infections, including but not limited to: uncontrollable ventricular arrhythmias, history of documented myocardial infarction within 3 months, uncontrollable epileptic dementia, unstable spinal compression, superior vena cava syndrome, extensive bilateral interstitial pulmonary disease by high-resolution computed tomography (HRCT), or any neurological or mental abnormalities which affect compliance.
• Human immunodeficiency virus (HIV) positive
• Pregnancy or lactation women
• Cannot be orally administered medication
• Subject with a tendency for gastrointestinal hemorrhage. Including: Black stool or hematemesis within 2 months; For subjects positive in occult test with unresected primary lesion, if the principle investigator in each center considers with possibility of gastrointestinal hemorrhage, the subject could not be enrolled.
• Subject with malignant pleural effusion need medical intervention.
• A history or evidence of hereditary hemorrhagic constitution or coagulation disorder that increases the risk of bleeding
• Subjects with central nerve system metastases
• Have been enrolled in other clinical trial with investigational drug treatment within the 4 weeks of start of study treatment
• For subject with bone metastases, palliative radiotherapy was given 4 weeks before enrollment (radiation field >5%).
• Any other disease or condition that the investigator considers not suitable for participating in this clinical trial.