Neo-adjuvant Chemotherapy in Locally Advanced Gastric Cancer

A Phase II Study of Neo-adjuvant Chemotherapy in Locally Advanced Gastric Cancer

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.

Study Overview

• Status: Completed
• Conditions: Stage T3-4NxM0 Gastric Cancer
• Intervention / Treatment: Drug: Docetaxel; Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 308433
    • Johns Hopkins Singapore International Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Docetaxel and Capecitabine in gastric cancer; 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.	Drug: Docetaxel; Docetaxel 60 mg/m2 IV on day 1; Drug: Capecitabine; Capecitabine 900 mg/m2 PO two times per day from day 1 to day 14 every 3 weeks for 2 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Pathological Response	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.	up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Median number of months participants alive at the time of observation. Calculated using Kaplan-Meier method.	up to 8 years
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.	Number of participants who experience Grade 3/4 neutropenia, Grade 3 nausea or Grade 3 diarrhea.	up to 5 years
Correlation of CGH and Gene Expression Profile and Their Changes After Chemotherapy With the Same Clinical Outcomes	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.	up to 5 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Investigators: Principal Investigator: Alex Chang, Johns Hopkins University

Publications and helpful links

General Publications

• Chang AY, Foo KF, Koo WH, Ong S, So J, Tan D, Lim KH. Phase II study of neo-adjuvant chemotherapy for locally advanced gastric cancer. BMJ Open Gastroenterol. 2016 Aug 23;3(1):e000095. doi: 10.1136/bmjgast-2016-000095. eCollection 2016.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: December 20, 2006
• First Submitted That Met QC Criteria: December 20, 2006
• First Posted (Estimate): December 21, 2006

Study Record Updates

• Last Update Posted (Actual): July 25, 2019
• Last Update Submitted That Met QC Criteria: May 31, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: gastric cancer, neo-adjuvant chemotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel; Capecitabine
• Other Study ID Numbers: JS 0420; NA_00044000 (Other Identifier: JHM IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No