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

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

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)