Low-Tox Vs Eox In Patients With Locally Advanced Unresectable Or Metastatic Gastric Cancer

Study Overview
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Brief Summary
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This is a randomized, parallel group, non-blinded phase III trial. Patients with advanced (locoregional or metastatic) gastric cancer not previously treated with chemotherapy for this stage will be randomized in a 1:1 ratio to receive low-TOX (arm A) or EOX (arm B). Randomization will be stratified by performance status (ECOG 0, 1 and 2).

Detailed Description
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Although the incidence of the adenocarcinoma of the stomach is slowly decreasing, gastric cancer represents the second worldwide cause of cancer death after lung cancer. In patients with advanced disease, chemotherapy improves survival and quality of life. Combinations of two or three drugs including a platin derivative (cisplatin or oxaliplatin), a fluoropyrimidine (5FU or capecitabine) and an anthracycline (usually epirubicin) have demonstrated superiority compared to single or double agent therapy and are the current standard. As of today there are no published studies comparing anthracycline-based to taxane-based three-drug regimens. The objective of the present study is to compare EOX as evaluated in REAL-2 to the low-TOX regimen consisting of docetaxel, oxaliplatin and capecitabine. Low-TOX is expected to be better tolerated than the original DCF regimen. The study will be performed in the HER2 negative patients.

Official Title
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A Randomized Phase III Study Of Low-Docetaxel Oxaliplatin, Capecitabine (Low-Tox) Vs Epirubicin, Oxaliplatin And Capecitabine (Eox) In Patients With Locally Advanced Unresectable Or Metastatic Gastric Cancer

Conditions
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Locally Advanced Unresectable Gastric Cancer, Metastatic Gastric Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Epirubicin
* Drug: Oxaliplatin
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent prior to beginning protocol specific procedures Male or female > 18 years of age Histologically proven diagnosis of adenocarcinoma of the stomach HER2 negative tumor or HER2+ tumors not qualifying for herceptin therapy Locally advanced (non resectable) or metastatic gastric cancer Presence of measurable disease with at least one measurable lesion by means of CT scan or MRI in not previously irradiated area(s) (according to RECIST criteria (version 1.1) Life expectancy of >/= 3 months ECOG performance status of 0-2 at study entry Neutrophils >/= 2.0 x 1000000000/L, platelets >/= 100 x 1000000000/L, and hemoglobin >/= 10 g/dL Bilirubin level either normal or </= 1.5 x ULN AST and ALT </= 2.5 X UNL (</= 5 x ULN if liver metastasis are present Alkaline phosphatase (ALP) </= 2.5 X ULN; patients with alkaline phosphatase > 2.5x ULN and AST and ALT </= 1.5 x ULN are equally eligible Serum creatinine < 1.5 x ULN. In presence border-line values, the calculated creatinine clearance should be >/= 60 mL/min Negative pregnancy test (if female in reproductive years) Effective contraception prior to study entry and for the duration of the study participation, for both male and female patients of child producing potential Able and willing to comply with scheduled visits, therapy plans and laboratory tests required in this protocol Exclusion Criteria: Previous chemotherapy, except adjuvant treatment administered at least 1 year before study entry Concurrent chronic systemic immune therapy Any investigational agent(s) 4 weeks prior to entry Clinically relevant coronary artery disease or a history of a myocardial infarction or a history of hypertension not controlled by therapy within the last 12 months Known hypersensitivity to study drugs. Known grade 3 or 4 allergic reaction to any of the components of the treatment Known drug abuse/ alcohol abuse Acute or subacute intestinal occlusion and any other significant chronic gastrointestinal disease that might interfere with absorption of oral treatment History of clinically relevant psychiatric disability precluding informed consent Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Pregnant or breastfeeding women Active uncontrolled infection(s) Positive for HIV serology and/or viral hepatitis B or C Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix. (Patients with a previous malignancy but without evidence of disease for ≥ 5 years will be allowed to enter the trial)

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel & Oxaliplatin & Capecitabine<br>Patients will receive cycles every 3 weeks of Docetaxel (35 mg/ m2, intravenous at days 1 and 8 by 1-hour infusion)and Oxaliplatin (80 mg/ m2, intravenous at day 1 by 2-hour infusion) and Capecitabine (750 mg/ m2, oral tablets of 500 and 150 mg, x2 daily for 2 weeks) | Drug: Docetaxel<br>* Powder for solution for infusion<br>* Other names: Taxotere 20 mg/mL;Drug: Oxaliplatin<br>* Powder for solution for infusion<br>* Other names: Eloxatin 5 mg/mL;Drug: Capecitabine<br>* Film coated tablets<br>* Other names: Xeloda 500 mg;|
| Experimental: Epirubicin & Oxaliplatin & Capecitabine<br>Patients will receive cycles every 3 weeks of Epirubicin (50 mg/ m2, intravenous on day 1 by 2-hour infusion)and Oxaliplatin (130 mg/ m2, intravenous on day 1 by 2-hour infusion) and Capecitabine (625 mg/ m2,oral tablets of 500 and 150 mg, x2 daily for 3 weeks) | Drug: Epirubicin<br>* Solution for infusion<br>* Other names: Farmorubicina 2mg/mL;Drug: Oxaliplatin<br>* Powder for solution for infusion<br>* Other names: Eloxatin 5 mg/mL;Drug: Capecitabine<br>* Film coated tablets<br>* Other names: Xeloda 500 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | To determine the progression free survival (PFS) of patients with locally advanced unresectable or metastatic gastric cancer treated with Docetaxel plus Oxaliplatin plus Capecitabine (Arm A) or with Epirubicin plus Oxaliplatin plus Capecitabine (Arm B) | Measured as the time from randomization to the date of local or regional progression, distant metastasis, second primary malignancy or death, assessed up to 18 months of follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | To assess overall survival (OS) of patients with locally advanced unresectable or metastatic gastric cancer treated with Docetaxel plus Oxaliplatin plus Capecitabine (Arm A) or with Epirubicin plus Oxaliplatin plus Capecitabine (Arm B) | Measured as the time from randomization to the date of death from any cause, assessed up to 18 months of follow up | 
| Objective Response Rate (CR + PR) according to RECIST 1.1 guideline | To assess objective response rate (CR+PR)of patients with locally advanced unresectable or metastatic gastric cancer treated with Docetaxel plus Oxaliplatin plus Capecitabine (Arm A) or with Epirubicin plus Oxaliplatin plus Capecitabine (Arm B) | Measured as the time from randomization, assessed up to 18 months of follow up | 
| Disease control rate: CR + PR + SD lasting > 12 weeks | To assess disease control rate of patients with locally advanced unresectable or metastatic gastric cancer treated with Docetaxel plus Oxaliplatin plus Capecitabine (Arm A) or with Epirubicin plus Oxaliplatin plus Capecitabine (Arm B) | Measured as the time from randomization, assessed up to 18 months of follow up | 
| Tolerability of the treatments evaluated in term of occurrence of: side effects graded according to the NCI-CTCAE scale (version 4.0); serious adverse reactions, expected and unexpected | To assess tolerability of the treatments of patients with locally advanced unresectable or metastatic gastric cancer treated with Docetaxel plus Oxaliplatin plus Capecitabine (Arm A) or with Epirubicin plus Oxaliplatin plus Capecitabine (Arm B) | Measured as the time from randomization, assessed up to 18 months of follow up |