Neo-adjuvant Chemotherapy in Locally Advanced Gastric Cancer

• ClinicalTrials.gov Identifier: NCT00414271
• Recruitment Status: Completed
• First Posted: December 21, 2006
• Results First Posted: July 25, 2019
• Last Update Posted: July 25, 2019
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Stage T3-4NxM0 Gastric Cancer	Drug: Docetaxel; Drug: Capecitabine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Neo-adjuvant Chemotherapy in Locally Advanced Gastric Cancer
• Study Start Date: January 2006
• Actual Primary Completion Date: October 2015
• Actual Study Completion Date: October 2015

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Pathological Response [ Time Frame: 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 :

1. Overall Survival [ Time Frame: up to 8 years ]
   Median number of months participants alive at the time of observation. Calculated using Kaplan-Meier method.
2. Progression-free Survival as Measured by Number of Participants Without Disease Progression. [ Time Frame: up to 5 years ]
3. 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. [ Time Frame: up to 5 years ]
   Number of participants who experience Grade 3/4 neutropenia, Grade 3 nausea or Grade 3 diarrhea.
4. Correlation of CGH and Gene Expression Profile and Their Changes After Chemotherapy With the Same Clinical Outcomes [ Time Frame: 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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Singapore

Johns Hopkins Singapore International Medical Center

Singapore, Singapore, 308433

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

• Principal Investigator: Alex Chang; Johns Hopkins University

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00414271
• Other Study ID Numbers: JS 0420; NA_00044000 ( Other Identifier: JHM IRB )
• First Posted: December 21, 2006
• Results First Posted: July 25, 2019
• Last Update Posted: July 25, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

gastric cancer, neo-adjuvant chemotherapy

Additional relevant MeSH terms:

Stomach Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Docetaxel; Capecitabine; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites