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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Gastric Adenocarcinoma

Intervention / Treatment
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* Drug: S1
* Drug: Paclitaxel
* Drug: Bevacizumab
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>S1+Paclitaxel (IV&IP)+Bevacizumab (IP) | Drug: S1<br>* 80-120 mg/day, PO, D1-14, every 21 days<br>* Other names: Tegafur Gimeracil Oteracil Potassium Capsule;Drug: Paclitaxel<br>* 20 mg/m2/day, IP, D1-3; 50 mg/m2, IV, D1; 70 mg/m2, IV, D8; every 21 days<br>* Other names: Paclitaxel Injection;Drug: Bevacizumab<br>* 200 mg, IP, D1, every 21 days<br>* Other names: Avastin ®;|
| Active Comparator: Control arm<br>S1+Oxaliplatin (IV) | Drug: S1<br>* 80-120 mg/day, PO, D1-14, every 21 days<br>* Other names: Tegafur Gimeracil Oteracil Potassium Capsule;Drug: Oxaliplatin<br>* 130 mg/m2, IV, D1, every 21 days<br>* Other names: ELOXATIN®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ascites response rate at 6 weeks | response of ascites at 6 weeks | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression-free survival,From 1st drug administration to the date of first progression or date of death (whichever occurs first) | 12 months | 
| OS | Overall survival, from enrollment until death from any cause | 2 years | 
| ORR | Objective response rate, the proportion of patients with reduction in tumor burden of a predefined amount | 12 months | 
| TTF | Time to treatment failure, from 1st drug administration to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death | 12 months | 
| Puncture free survival | Puncture free survival time, from the first puncture to secondary puncture | 12 months | 
| Volume of drainage | Volume of drainage | 12 months | 
| Adverse events | Adverse events | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Carcinoma, Malignant Ascites, Intraperitoneal Chemotherapy, Bevacizumab