Neo-adjuvant Chemotherapy in Locally Advanced Gastric Cancer

Phase 2

Completed

Conditions: Stage T3-4NxM0 Gastric Cancer

Interventions: Drug: Docetaxel
Drug: Capecitabine

Registration Number: NCT00414271

Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary: Thymidylate Synthase (TS) is a key enzyme in the synthesis of DNA and the target enzyme inhibited by 5-fluorouracil (5-FU). TS level in the tumour cells has been reported as predictive to response to 5-FU and a prognostic factor in colorectal and gastric cancer patients. We plan to study TS by immunohistochemistry (IHC) in the paraffin blocks of tumour tissue.

A combined comparative genomic hybridization (CGH) and expression microarray analysis of gastric cancer specimens before and after neoadjuvant chemotherapy. CGH will be performed using standard technique routinely done in Dr Patrick Tan's laboratory at the National Cancer Centre, which determines the gain or loss of DNA copies of each chromosome. Total RNA will be extracted from at least one biopsy sample which contains at least 50% cancer cells by homogenization of the tumour tissue and tri-sol method. 5 ug of RNA were amplified and hybridized with the C-DNA microarrays of 18K targets.

Primary Objective 1. Feasibility and safety of pre-operative chemotherapy in locally advanced gastric cancer.

Secondary Objective

1. Complete clinical and pathological response rates to pre-operative chemotherapy in locally advanced gastric cancer

2. Complete resection rate.

3. Time to recurrence, disease free and overall survival

4. Correlation of clinical outcome with (Runt-related transcription factor) RUNX-3 methylation status and Thymidylate synthetase in the tumor tissue.

5. Correlation of CGH and gene expression profile and their changes after chemotherapy with clinical outcome.

Patients may be included in the study only if they meet all of the following criteria:

Age at least 18 years. Histologic or cytologic diagnosis of adenocarcinoma of stomach or gastric cardia (Siewert Classification Type III) Preoperative Stage T3-4NxM0 by endoscopic ultrasound, CT of the abdomen/pelvis and laparoscopy. (CT of the chest if it is a cardia lesion).

Absence of malignant cells in peritoneal lavage fluid during laparoscopic examination.

Patients must not have received any prior chemotherapy or hormonal therapy for the treatment of gastric cancer.

Karnofsky performance status of 70 or higher. Estimated life expectancy of at least 12 weeks.

Adequate organ function including the following:

- Bone marrow: White blood cells (WBC) at least 3.5 x 109/L Absolute neutrophil (segmented and bands) count (ANC) at least 1.5 x 109/L Platelets at least 100 x 109/L Haemoglobin at least 9g/dL

- Hepatic: Bilirubin within upper limit of normal (ULN), Aspartate transaminase (ALT) or Alanine transaminase (AST) not more than 2.5x ULN Alkaline phosphatase not more than 2.5x ULN.

- Renal: creatinine not more than 1.5x ULN Signed informed consent by patient or legal representative. Patients with reproductive potential must use an approved contraceptive method if appropriate (eg, intrauterine device, birth control pills, or barrier device) during and for three months after the study. Females with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

The study plans to recruit 30 patients in 12-18 months.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

Inclusion Criteria

Age greater than or equal 18 years.
Histologic or cytologic diagnosis of adenocarcinoma of stomach or gastric cardia (Siewert Classification Type III)
Preoperative Stage T3-4NxM0 by endoscopic ultrasound, CT of the abdomen/pelvis and laparoscopy. (CT of the chest if it is a cardia lesion).
Absence of malignant cells in peritoneal lavage fluid during laparoscopic examination.
Patients must not have received any prior chemotherapy or hormonal therapy for the treatment of gastric cancer.
Karnofsky performance status of 70 or higher.
Estimated life expectancy of at least 12 weeks.
Adequate organ function including the following:
Bone marrow:
- White blood cells (WBC) greater than or equal 3.5 x 109/L
- Absolute neutrophil (segmented and bands) count (ANC) greater than or equal 1.5 x 109/L
- Platelets greater than or equal 100 x 109/L
- Haemoglobin greater than or equal 9g/dL
Hepatic:
- Bilirubin within upper limit of normal (ULN),
- ALT or AST less than or equal 2.5x ULN
- Alkaline phosphatase less than or equal 2.5x ULN.
Renal:
- creatinine less than or equal 1.5x ULN
Signed informed consent by patient or legal representative.
Patients with reproductive potential must use an approved contraceptive method if appropriate (eg, intrauterine device, birth control pills, or barrier device) during and for three months after the study. Females with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria

Prior treatment for locally advanced or metastatic gastric cancer. Any metastatic disease will render patient ineligible according to American Joint Committee on Cancer (AJCC) staging manual. (See appendix 11.4).
Treatment within the last 30 days with any investigational drug.
Concurrent administration of any other cancer therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
Pregnancy.
Breast-feeding.
Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
Poorly controlled diabetes mellitus with fasting blood sugar > 18 mmol/L(mM).
Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
History of significant neurological or mental disorder, including seizures or dementia.
History of hypersensitivity to drugs formulated in Tween 80, the vehicle used for commercial docetaxel formulations.
History of hypersensitivity to 5-fluorouracil

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Docetaxel and Capecitabine in gastric cancer	Docetaxel	Intravenous docetaxel 60 mg/m2 on day 1 and oral capecitabine 900 mg/m2 two times per day from day 1 to day 14 every 3 weeks for 2 cycles.
Docetaxel and Capecitabine in gastric cancer	Capecitabine	Intravenous docetaxel 60 mg/m2 on day 1 and oral capecitabine 900 mg/m2 two times per day from day 1 to day 14 every 3 weeks for 2 cycles.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Pathological Response	up to 5 years	Number of participants who completed neoadjuvant chemotherapy and underwent repeat CT and endoscopic ultrasound (EUS) with pathological complete response (pCR), partial response in the primary tumor, stable disease or progressive disease as defined by EUS criteria.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	up to 8 years	Median number of months participants alive at the time of observation. Calculated using Kaplan-Meier method.
Progression-free Survival as Measured by Number of Participants Without Disease Progression.	up to 5 years
Feasibility and Safety of Pre-operative Chemotherapy in Locally Advanced Gastric Cancer as Assessed by Number of Participants Who Experienced Adverse Events Grade 3 or Higher as Defined by CTCAE.	up to 5 years	Number of participants who experience Grade 3/4 neutropenia, Grade 3 nausea or Grade 3 diarrhea.
Correlation of CGH and Gene Expression Profile and Their Changes After Chemotherapy With the Same Clinical Outcomes	up to 5 years	Initially, we also planned to study the thymidylate synthetase expression, methylation of RUNX-3 gene\[24\] and comprehensive genomic hybridization\[25\] before and after chemotherapy to look for biomarkers of response and prognostic indication. But due to the lack of pCR and the small number of patients enrolled, we stopped the correlative studies.