Genotype Guided Chemotherapy in Gastric Cancer Patients

TSER Genotype Guided Chemotherapy in Metastatic Gastric Cancer Patients: A Phase II Study in China

In gastric cancer patients treated with 5-FU and cisplatin, higher tumor TS levels were associated with a less favorable response (29% vs. 68%; p=0.024). Similarly, in a study in which patients were treated with high dose 5-FU, patients with high TS expression had a response rate of only 12.5%. Conversely a response rate of 92.9% was observed in patients with low tumor TS expression. A longer but not statistically significant survival advantage was observed in patients with the TSER*2 allele compared with the TSER*3/*3 patients. Additionally, a review by Patel et al. identified approximately 20 gastric cancer studies that have found a positive association between TSER genotype and clinical response (in either direction). Therefore, the primary goal of this proposal is to prospectively genotype patients, select patients with "good risk" TSER genotypes (TSER*2*/*2 or *2/*3) and treat them with a standard 5-FU containing regimen (FOLFOX) in order to improve clinical outcomes, while randomize patients with the "poor risk" TSER genotype (*3/*3) to either the standard 5-FU containing regimen or another non-5-FU-based regimen (docetaxel/cisplatin).

Study Overview

• Status: Completed
• Conditions: Metastatic Gastric Cancer
• Intervention / Treatment: Genetic: TSER

• Study Type: Interventional
• Enrollment (Actual): 330
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410005
      • Institute of Clinical Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed metastatic adenocarcinoma of the stomach.
2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. See section 9.2 for the evaluation of measurable disease.
3. No prior therapy for metastatic disease. Prior neo-adjuvant or adjuvant therapy is permitted if the disease free interval has been longer than 12 months.
4. Age between 18 and 70 years. Because no dosing or adverse event data are currently available on the use of these regimens in patients <18 years of age, children are excluded from this study.
5. Life expectancy of greater than 3 months.
6. ECOG performance status < 2 (Karnofsky >60%; see Appendix A).

7. Patients must have normal organ and marrow function as defined below:

   • Leukocytes >3,000/microliter
   • Absolute neutrophil count >1,500/microliter
   • Platelets >100,000/microliter
   • Total bilirubin < 1.5 x ULN
   • AST(SGOT)/ALT(SGPT) <2.5 x ULN if not liver metastases < 5 x ULN if known liver metastases
   • Creatinine clearance <1.5 x ULN

8. Not pregnant. Not breast feeding. If the patient or partner is of childbearing potential, the couple will use adequate birth control in accordance with local IRB policies:

   For woman of childbearing potential:

   Patient must have negative blood pregnancy test. If sexually active, woman must either be post-menopausal (over age 50 and have not had a menstrual period for one year or more, or blood FSH level in the post-menopausal range) OR agree to use appropriate contraceptive measures for the duration of the study and for 21 days after stopping study treatment. The only birth control methods for women that are acceptable for this study are: (1) surgical sterilization (previous removal of the uterus or both ovaries or a tubal ligation) OR (2) an intrauterine device (IUD), (3) double barrier methods, (4) oral contraceptives.

   For men:

   Medically acceptable contraceptives include: (1) surgical sterilization, or (2) a condom used with a spermicide. If the female partner becomes pregnant while patient is on treatment or within 21 days after stopping treatment, the study physician must be informed.

9. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients may not be receiving any other chemotherapy agents.
2. Patients with known active brain metastases. Patients with treated brain metastases are permitted if stable off steroids for at least 30 days. A screening head CT/MRI is not required in asymptomatic patients for this protocol.
3. History of allergic reactions to 5-FU, oxaliplatin, docetaxel, or cisplatin.
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
5. Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the chemotherapies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: TSER *2/*2 *2/*3; Patients with TSER *2/*2 *2/*3 genotypes will be assigned to this group and receive standard chemotherapy contains fluorouracil. (FOLFOX 6/XELOX/SOX)	Genetic: TSER; TS gene will be genotyped for each patients prior to chemotherapy. Patients will be assigned to different arms according to specific TSER genotype.; Other Names: TSER genotypes: *2/*2 *2/*3 *3/*3
Other: TSER*3/*3 (fluorouracil); Patients with TSER*3/*3 genotype will be randomly assigned to fluorouracil group (FOLFOX 6/XELOX/SOX) or non-fluorouracil group (DC or DO).	Genetic: TSER; TS gene will be genotyped for each patients prior to chemotherapy. Patients will be assigned to different arms according to specific TSER genotype.; Other Names: TSER genotypes: *2/*2 *2/*3 *3/*3
Other: TSER*3/*3 (non-fluorouracil); Patients with TSER*3/*3 genotype will be randomly assigned to fluorouracil group (FOLFOX 6/XELOX/SOX) or non-fluorouracil group (DC or DO).	Genetic: TSER; TS gene will be genotyped for each patients prior to chemotherapy. Patients will be assigned to different arms according to specific TSER genotype.; Other Names: TSER genotypes: *2/*2 *2/*3 *3/*3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease control rate	Determine whether the disease control rate (DCR) at 6 and 12 weeks in TSER*3/*3 patients with metastatic gastric cancer will be increased by using a non fluoropyrimidine containing regimen compared to fluoropyrimidine-containing regimens.	6 and 12 weeks after the first chemotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time to progression	TTP is defined in this study as: "The length of time from the date of the start of treatment for gastric cancer until the disease starts to get worse or spread to other parts of the body."	2 years maximum
median overall survival	median overall survival is defined in this study as: "The length of time from the start of treatment for a disease that half of the patients in a group of patients diagnosed with the disease are still alive."	2 years maximum

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
drug toxicities	Drug toxicities will be recorded and evaluated by NCI CTCAE v3.0.	2 years maximum

Collaborators and Investigators

• Sponsor: Central South University

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: July 21, 2014
• First Submitted That Met QC Criteria: July 29, 2014
• First Posted (Estimate): July 30, 2014

Study Record Updates

• Last Update Posted (Actual): November 18, 2019
• Last Update Submitted That Met QC Criteria: November 15, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms
• Other Study ID Numbers: 1000 Talents-CSU-GC; 1000 Plan (Other Identifier: 1000 Plan Program)