Pre-Operative Or Peri-Operative Dox Regimen In Patients With Locally Advanced Resectable Gastric Cancer

Study Overview
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Brief Summary
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Study design: Multicenter, randomized, open label phase II study Arm A: DOX 4 cycles - Surgery - Follow-up Arm B: DOX 2 cycles - Surgery - DOX 2 cycles - Follow-up Population: Male or female, 18-75 years of age, with a diagnosis of histologically confirmed, potentially resectable adenocarcinoma of the stomach. Sample Size: Planned sample size is 90 patients, 45 patients for each arm (p0=50%, p1=80%, alpha=0.05 (two sides), beta=0.2) Treatment Plan: Treatment will be administered for 4 and 2 cycles before surgery in arm A and B, respectively, and in arm B for a further 2 cycles after surgery unless progression or unacceptable toxicity occurs, or a patient refuses treatment. In such cases patients will go off treatment. 3-6 weeks after the end of the fourth (arm A) or second (arm B) preoperative cycle, patients will undergo surgery. After surgery 3-6 weeks from surgery patients in arm B will receive 2 more cycles. DOX: Docetaxel 35 mg/m2 day 1 and 8 Oxaliplatin 80 mg/m2 day 1 Capecitabine 750 mg/m2 x 2 daily for 2 weeks Cycles repeated every 3 weeks Evaluation criteria: Tumor assessment will be performed according to the RECIST criteria (version 1.1). Duration of Study: Overall study duration: 07/2010- 03/2017 Planned study duration per patient: 5 years

Detailed Description
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Title: A randomised phase II study of pre-operative or peri-operative docetaxel, oxaliplatin, capecitabine (DOX) regimen in patients with locally advanced resectable gastric cancer. Clinical Phase: II Study Objectives: Primary: The percentage of patients receiving all the planned chemotherapeutic cycles. Secondary: Downstaging according to Recist criteria pT1-3 vs pT0. Safety: number of patients with grade 3-4 toxicity The role of PET Scan as predictor of response Curative vs palliative surgery TTP OS Diagnostic correlation between the various staging methods Possible correlations between CT scan, CT/PET, laparoscopy; Molecular markers related to toxicity: DPYD, MTHFR, TS, XPD, ERCC1, XRCC1; Molecular markers related to prognosis: TYMS, GSTP1, COX-2, RUNX3, methylation profile (Cox2, hMLH1, MGMT); Molecular markers related to therapy response: TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1, GSTM1, GSTT1, ABCB1, methylation profile (Cox2, hMLH1, MGMT), whole genome arrayCGH. Study design: Multicenter, randomized, open label phase II study Arm A: DOX 4 cycles - Surgery - Follow-up Arm B: DOX 2 cycles - Surgery - DOX 2 cycles - Follow-up Population: Male or female, 18-75 years of age, with a diagnosis of histologically confirmed, potentially resectable adenocarcinoma of the stomach. Sample Size: Planned sample size is 90 patients, 45 patients for each arm (p0=50%, p1=80%, alpha=0.05 (two sides), beta=0.2) Treatment Plan: Treatment will be administered for 4 and 2 cycles before surgery in arm A and B, respectively, and in arm B for a further 2 cycles after surgery unless progression or unacceptable toxicity occurs, or a patient refuses treatment. In such cases patients will go off treatment. 3-6 weeks after the end of the fourth (arm A) or second (arm B) preoperative cycle, patients will undergo surgery. After surgery 3-6 weeks from surgery patients in arm B will receive 2 more cycles. DOX: Docetaxel 35 mg/m2 day 1 and 8 Oxaliplatin 80 mg/m2 day 1 Capecitabine 750 mg/m2 x 2 daily for 2 weeks Cycles repeated every 3 weeks Evaluation criteria: Tumor assessment will be performed according to the RECIST criteria (version 1.1). Duration of Study: Overall study duration: 07/2010- 03/2017 Planned study duration per patient: 5 years

Official Title
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A Randomised Phase Ii Study Of Pre-Operative Or Peri-Operative Docetaxel, Oxaliplatin, Capecitabine (Dox) Regimen In Patients With Locally Advanced Resectable Gastric Cancer

Conditions
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Gastric Cancer, Locally Advanced Malignant Neoplasm

Intervention / Treatment
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* Other: DOX 4 cycles - Surgery
* Other: DOX 2 cycles - Surgery - DOX 2 cycles


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consents Male or female 18-75 years of age Diagnosis of histologically confirmed, potentially resectable adenocarcinoma of the stomach cT3 subserosal - cT4a - cT4b (7th edition UICC TNM) or bulky lymph node metastases independently of T ECOG performance status of 0-1 at study entry Laboratory requirements (≤ 7 days prior chemotherapy start): Hematology: I) Neutrophils > 1.5 x 109 /L II) Platelets > 100 x 109 /L III) Hemoglobin > 10g/dL Hepatic function I) Total bilirubin < 1.25 UNL II) AST (SGOT) and ALT (SGPT) < 2.5xUNL III) Alkaline phosphatase < 2.5xUNL Renal function I) Creatinine <1.5 UNL In the event of border-line values, the calculated creatinine clearance should be > 60 mL/min; Written informed consent signed and dated before randomization procedures, including expected cooperation of patients for treatment and follow-up, must be obtained and documented according to local regulatory requirements. Effective contraception for both male and female patients if the risk of conception exists Exclusion Criteria: Early gastric cancer (if N0) T2 (according to 7th edition of UICC TNM) if N0 Linitis plastica Positive peritoneal cytology Distant metastases Neoplasm involving the gastro-esophageal junction Pertoneal involvement Concurrent chronic systemic immune therapy Any investigational agent(s) administered 4 weeks prior to entry Clinically relevant coronary artery disease, a history of myocardial infarction or of hypertension not controlled by therapy within the last 12 months Known grade 3 or 4 allergic reaction to any of the components of the treatment Known drug abuse/alcohol abuse Legal incapacity or limited legal capacity Medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent Women who are pregnant or breastfeeding Acute or subacute intestinal occlusion 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
Maximum Age: 75 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: Arm A<br>DOX 4 cycles - Surgery - Follow-up DOX: Docetaxel 35 mg/m2 day 1 and 8 by one hour infusion; Oxaliplatin 80 mg/m2 day 1 by two hours infusion; Capecitabine 750 mg/m2 x 2 daily for 2 weeks, per OS. Treatment should be administered for 4 cycles before surgery. Each cycle will be repeated every 3 weeks. | Other: DOX 4 cycles - Surgery<br>* DOX 4 cycles - Surgery<br>|
| Experimental: Arm B<br>DOX 2 cycles - Surgery - DOX 2 cycles - Follow-up DOX: Docetaxel 35 mg/m2 day 1 and 8 by one hour infusion; Oxaliplatin 80 mg/m2 day 1 by two hours infusion; Capecitabine 750 mg/m2 x 2 daily for 2 weeks, per OS. Treatment should be administered for 2 cycles before surgery and for further 2 cycles after surgery, unless progression of disease or unacceptable toxicity occurs, or patient refusal. In these cases patients will go off treatment. Each cycle will be repeated every 3 weeks. | Other: DOX 2 cycles - Surgery - DOX 2 cycles<br>* DOX 2 cycles - Surgery - DOX 2 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the difference in percentage of patients receiving all the planned chemotherapeutic cycles between the two arms. |  | 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of tumors downstaged at the diagnosis | To determine the percentage of tumors downstaged at the diagnosis, compared with the pathological stage detected at the time of surgery (according to Recist criteria) | 7 years | 
| Treatment tolerability and safety and tumor response in patients with pathological stage pT1-3 vs pT0 | Comparation of treatment tolerability and safety and tumor response between patients with pathological stage pT1-3 vs pT0 (detected at the time of surgery) | 7 years | 
| Number of patients with adverse events of grade 3-4 as a measure of safety and tolerability |  | 7 years | 
| Diagnostic capability of PET | Evaluation of the role of PET as a tool to detect tumor response | 7 years | 
| Efficacy comparation between curative vs palliative surgery |  | 7 years | 
| Time to progression |  | 7 years | 
| Overall survival |  | 7 years | 
| Diagnostic capability of CT scan, CT/PET and laparoscopy | Evaluation of possible correlations between the diagnostic techniques CT scan, CT/PET and laparoscopy | 7 years | 
| Biological profile of treatment toxicity | Biological detection of molecular markers related to treatment toxicity (DPYD, MTHFR, TS, XPD, ERCC1, XRCC1) | 7 years | 
| Biological profile of treatment prognosis | Biological detection of molecular markers related to treatment prognosis (TYMS, GSTP1, COX-2, RUNX3, methylation profile (Cox2, hMLH1, MGMT)) | 7 years | 
| Biologcal profile of treatment response | Biological detection of molecular markers related to therapy response (TYMS, DPYD, MTHFR, OPRT, ERCC1, XRCC1/2/3, GSTP1, GSTM1, GSTT1, ABCB1, methylation profile (Cox2, hMLH1, MGMT), whole genome arrayCGH) | 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally, Advanced, Resectable, Gastric Cancer