Individualized Intraperitoneal and System Chemotherapy Versus System Chemotherapy as First-line Chemotherapy for AGC

Study Overview
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Brief Summary
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Tumor messenger ribonucleic acid (mRNA) expression levels may have a promising role as potential predictive biomarkers for chemotherapy. Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Intraperitoneal chemotherapy is widely accepted strategy in the treatment of peritoneal dissemination. In this study, our aim is to evaluate the impact of individualized selection of chemotherapeutics and intraperitoneal combined with system chemotherapy on overall survival, disease free survival, response rate, and safety of advanced gastric cancer patients.

Official Title
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An Open-label, Randomized, Phase III, Multicenter Clinical Trial Comparing the Efficacy and Safety of Individualized Intraperitoneal and System Chemotherapy Versus System Chemotherapy as First-line Chemotherapy for Advanced Gastric Cancer

Conditions
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Stomach Neoplasms, Chemotherapy Effect, Chemotherapeutic Toxicity

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Oxaliplatin
* Drug: Cisplatin
* Drug: Irinotecan
* Drug: Pemetrexed
* Drug: S1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction with inoperable locally advanced or metastatic disease, not amenable to curative therapy. Patients must have measurable disease, according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1), assessed using imaging techniques (CT or MRI). Patients must have enough tumor tissue for mRNA expression test. Women of childbearing potential must be non-pregnant (negative pregnancy test within 72 hours prior to chemotherapy, postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential) and nonlactating, and men and women must be willing to exercise an effective form of birth control (abstinence/contraception) while on study and for 6 months after therapy completed Eastern Cooperative Oncology Group (ECOG) Performance status 0, 1 or 2. Absolute neutrophil count (ANC) >=1,500/ul Platelets (PLT) >=75,000/ul Serum bilirubin <= 1.5 × upper limit of normal (ULN) Aspartate transaminase (AST) or alanine aminotransferase (ALT) <= 2.5 × ULN (or <= 5 × ULN in patients with liver metastases) Alkaline phosphatase <= 2.5 × ULN (or <= 5 × ULN in patients with liver metastases, or <= 10 × ULN in patients with bone but no liver metastases) Albumin >= 25 g/L. Creatinine clearance >= 60 mL/min. Life expectancy of at least 3 months. Signed informed consent. Exclusion Criteria: Previous chemotherapy for advanced/metastatic disease (prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant/neoadjuvant therapy and enrolment into the study; the total dose of cisplatin should be less than 300mg/m^2). Patients with active (significant or uncontrolled) gastrointestinal bleeding. Residual relevant toxicity resulting from previous therapy (with the exception of alopecia), e.g. neurological toxicity ≥ grade 2 NCI-CTCAE 4.0. Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma. History of documented congestive heart failure; angina pectoris requiring medication;evidence of transmural myocardial infarction on ECG; poorly controlled hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg); clinically significant valvular heart disease; or high risk uncontrollable arrhythmias. Baseline left ventricular ejection fraction (LVEF) < 50% (measured by echocardiography or MUGA). Patients with dyspnoea at rest due to complications of advanced malignancy or other disease, or who require supportive oxygen therapy. Patients receiving chronic or high dose corticosteroid therapy. (Inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed). Clinically significant hearing abnormality. Known dihydropyrimidine dehydrogenase (DPD) deficiency. History or clinical evidence of brain metastases. Serious uncontrolled systemic intercurrent illness, e.g. infections or poorly controlled diabetes. Positive serum pregnancy test in women of childbearing potential. Received any investigational drug treatment within 4 weeks of start of study treatment. Radiotherapy within 4 weeks of start of study treatment (2 week interval allowed if palliative radiotherapy given to bone metastatic site peripherally and patient recovered from any acute toxicity;prior adjuvant radiotherapy is allowed if complete at least 6 months ). Major surgery within 4 weeks of start of study treatment, without complete recovery. Patients with known active infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV). Known hypersensitivity to any of the study drugs.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individualized Group<br>mRNA levels of BRCA1, topoisomerase I (TOPO1), and thymidylate synthase (TS) were assessed in tumor tissue. Chemotherapeutic agents were selected based on the mRNA levels. Patients with high level BRCA1 will receive intraperitoneal docetaxel (15mg/m^2, d1, d15, q4w), intravenous docetaxel (30mg/m^2, d1, d15, q4w), and oral S-1 (40mg/m^2, d1-14, q4w). Patients with low level BRCA1 will receive intraperitoneal cisplatin (25mg/m^2, d1, d15, q4w), intravenous oxaliplatin (75mg/m^2, d1, d15, q4w), and oral S-1 (40mg/m^2, d1-14, q4w). Patients with middle level BRCA1 and high level TOPO1 will receive intraperitoneal irinotecan (45mg/m^2, d1, d15, q4w), intravenous docetaxel (90mg/m^2, d1, d15, q4w), and oral S-1 (40mg/m^2, d1-14, q4w). Patients with middle level BRCA1, low or middle level TOPO1, and low level TS will receive intraperitoneal pemetrexed (150mg/m^2, d1, q3w), and intravenous pemetrexed (350mg/m^2, d1, q3w). | Drug: Docetaxel<br>* intraperitoneal and/or intravenous<br>Drug: Oxaliplatin<br>* intravenous<br>Drug: Cisplatin<br>* intraperitoneal<br>Drug: Irinotecan<br>* intraperitoneal and/or intravenous<br>Drug: Pemetrexed<br>* intraperitoneal and/or intravenous<br>Drug: S1<br>* oral<br>|
| Active Comparator: Control Group<br>mRNA levels of BRCA1, TOPO1, and TS were assessed in tumor tissue for every enrolled patients. Patients in control group will receive intravenous docetaxel (45mg/m^2, d1, d15, q4w), and oral S-1 (40mg/m^2, d1-14, q4w). | Drug: Docetaxel<br>* intraperitoneal and/or intravenous<br>Drug: S1<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | the follow-up visit of PFS will be performed every 6 weeks | up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS means that from the first dose of treatment drug to death or lost, the follow-up visit will be performed every 3 months till death or lost | up to 2 years | 
| Objective Response Rate | CT/MRI will be performed every 2 cycles of treatment for efficacy evaluation | up to 24 weeks | 
| Adverse Events | participants will be followed for the duration of hospital stay | up to 1 months |