Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal Junction (GEJ) Tumors

Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal (GEJ) Tumors: A Phase II Study

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00515216

Enrollment

Registered

2007-08-13

Start date

2007-08-31

Completion date

2013-11-30

Last updated

2016-01-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Esophageal Neoplasms, Stomach Neoplasms

Keywords

Phase II, Gastric cancer, Gastroesophageal cancer, Metastatic, FOLFOX, Thymidylate synthase, Pharmacogenomic

Brief summary

This study is for patients who have stomach cancer or cancer of the lower part of the esophagus that has spread to other organs. There are many different chemotherapy treatments for this type of cancer. At the present time, there is no general agreement on the way to choose the most beneficial therapy for an individual patient. Patients with different genetic backgrounds may respond differently to the same chemotherapy treatments. In this study the investigators will use a certain genetic difference in an important gene (thymidylate synthase or TS gene) to see whether treating patients who have a particular type of that gene will respond better to a standard chemotherapy regimen. The investigators are hoping that by treating patients according to their genes, that they may respond to treatment of their cancer better and it will help the investigators choose cancer treatments better in the future.

Detailed description

Gastric and gastroesophageal junction (GEJ) cancers are a leading cause of cancer mortality. Despite the development of newer chemotherapies, the response rates and median survival in patients with these tumors has remained essentially stagnant. Defining host and molecular/biologic tumor characteristics to customize treatment may lead to improved survival outcomes. Retrospective studies have identified genetic markers that predict treatment outcome. However, there have been no prospective studies in gastric and GEJ cancer evaluating the clinical utility of these genetic factors. We hypothesize that genomically based treatment will improve the expected response rate in patients with gastric and GEJ cancers. We propose a prospective, multi-institutional Phase II clinical trial testing a germline polymorphism in the thymidylate synthase (TS) gene, the number of tandem repeats in the TS enhancer region (TSER) as a treatment selection marker. The polymorphic variant conferring three tandem repeats (TSER\*3) has been associated with 5-FU resistance due to high tumor TS expression in comparison to the TSER\*2 variant (two tandem repeats). The TSER\*3 polymorphism is common (allelic frequency of 0.5-0.8). In the proposed study, we will prospectively genotype patients with gastric and GEJ cancers. Patients who are expected to be 5-FU sensitive (carrying a TSER\*2 allele) will receive a 5-FU containing regimen (5-FU, leucovorin, oxaliplatin). Patients who are expected to be 5-FU resistant (homozygous for TSER\*3) will not be included in the study. In completing this study, we will determine whether treatment selection based on germline TSER polymorphism status improves the response rate in patients with metastatic gastric and GEJ tumors. Additional correlative studies are proposed to identify confounding factors that may alter the expected outcomes of this treatment approach.

Interventions

DRUG5-fluorouracil

DRUGOxaliplatin

DRUGLeucovorin

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patients must have histologically or cytologically confirmed adenocarcinoma of the stomach or gastroesophageal junction. * Patients must have measurable disease. * No prior therapy for metastatic disease. Prior neo-adjuvant or adjuvant therapy is permitted if the disease free interval has been longer than 6 months. * Age ≥18 years. * Life expectancy of greater than 3 months. * ECOG (Eastern Cooperative Oncology Group) performance status greater than 2 (Karnofsky greater than 60%). * Patients must have normal organ and marrow function. * Not pregnant. Not breast feeding. * Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

* Patients may not be receiving any other chemotherapy agents. * Patients with known active brain metastases. Patients with treated brain metastases are permitted if stable off steroids for at least 30 days. * History of allergic reactions to 5-FU or oxaliplatin. * Uncontrolled intercurrent illness. * Patients with immune deficiency.

Design outcomes

Primary

Measure	Time frame	Description
Overall Response Rate (ORR)	2 years	* ORR = complete response + partial response * Complete response - disappearance of all target and non-target lesions * Partial response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter

Secondary

Measure	Time frame	Description
Progression-free Survival (PFS)	4 years	Progressive disease - at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions
Disease Control Rate (DCR)	2 years	DCR - complete response, partial response, and stable disease * Complete response - disappearance of all target and non-target lesions * Partial response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter * Stable disease - neither sufficient shrinkage to qualify for partial response not sufficient increase to qualify for progressive disease
Overall Survival	4 years	—
Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	4 years	This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G\>C (rs34743033) gene had a partial tumor response.
Genetic Polymorphisms That May Alter Treatment Outcomes (Stable Disease)	4 years	This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G\>C (rs34743033) gene had stable disease.
Tumor Specific Changes That May Alter Treatment Outcomes	4 years	—

Countries

United States

Participant flow

Recruitment details

This study opened to participant enrollment in June 2008 and closed to participant enrollment in October 2010.

Participants by arm

Arm	Count
Oxaliplatin/Leucovorin/5-FU Good risk patients with the TSER\2/\2 or \2/\3 genotype or low TS expression genotype received treatment of oxaliplatin, leucovorin given over 2 hours along with 5-FU given as intravenous push followed by 5-FU given as intravenous infusion of 46 hours. This treatment was repeated every 2 weeks.	26
Total	26

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Oxaliplatin/Leucovorin/5-FU
Age, Continuous	56 years
ECOG Performance Status 0	5 participants
ECOG Performance Status 1	13 participants
ECOG Performance Status 2	8 participants
Incidence of prior neoadjuvant or adjuvant therapy (>6 months)	8 percentage of participants
Primary tumor type Gastric	19 participants
Primary tumor type Gastroesophageal junction	7 participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants
Race (NIH/OMB) White	23 Participants
Region of Enrollment United States	26 participants
Sex: Female, Male Female	10 Participants
Sex: Female, Male Male	16 Participants
TSER genotypes TSER2/2	5 participants
TSER genotypes TSER2/3	21 participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	20 / 25
serious Total, serious adverse events	0 / 25

Outcome results

Primary

Overall Response Rate (ORR)

* ORR = complete response + partial response * Complete response - disappearance of all target and non-target lesions * Partial response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter

Time frame: 2 years

Arm	Measure	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Overall Response Rate (ORR)	39.1 percentage of participants

Secondary

Disease Control Rate (DCR)

DCR - complete response, partial response, and stable disease * Complete response - disappearance of all target and non-target lesions * Partial response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter * Stable disease - neither sufficient shrinkage to qualify for partial response not sufficient increase to qualify for progressive disease

Time frame: 2 years

Arm	Measure	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Disease Control Rate (DCR)	95.7 percentage of participants

Secondary

Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)

This outcome looks at what genotypes of the MDR1 c.3435C\>T (rs1045642) gene had a partial response.

Time frame: 4 years

Population: 9 out of 25 participants had a partial response.

Arm	Measure	Group	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	C/C	0 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	C/T	9 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	T/T	0 participants

Secondary

Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)

This outcome looks at what genotypes of the TYMS 5'-UTR TSER + G\>C (rs34743033) gene had a partial tumor response.

Time frame: 4 years

Population: 9 out of 25 participants had a partial response.

Arm	Measure	Group	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	TYMS, TSER2/2	5 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	TYMS, TSER2/3 (G)	2 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	TYMS, TSER2/3 (C)	2 participants

Secondary

Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)

This outcome looks at what genotypes of the TYMS 3'-UTR 1494delTTAAAG(6 bp) (rs34489327) gene had a partial tumor response.

Time frame: 4 years

Population: 9 out of 25 participants had a partial response.

Arm	Measure	Group	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	+6 bp/+6 bp	5 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	+6 bp/-6 bp	4 participants

Secondary

Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)

This outcome looks at what genotypes of the ERCC1 c.354C\>T (rs11615) gene had a partial tumor response.

Time frame: 4 years

Population: 9 out of 25 participants had a partial response.

Arm	Measure	Group	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	C/C	2 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	C/T	4 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	T/T	3 participants

Secondary

Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)

This outcome looks at what genotypes of the ERCC2 c.2251A\>C (rs13181) gene had a partial response.

Time frame: 4 years

Population: 9 out of 25 participants had a partial response.

Arm	Measure	Group	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	A/A	5 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	A/C	3 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	C/C	1 participants

Secondary

Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)

This outcome looks at what genotypes of the GSTP1 c.313A\>G (rs1695) gene had a partial response.

Time frame: 4 years

Population: 9 out of 25 participants had a partial response.

Arm	Measure	Group	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	A/A	4 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	A/G	3 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	G/G	2 participants

Secondary

Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)

This outcome looks at what genotypes of the XRCC1 c.1196G\>A (rs25487) gene had a partial response.

Time frame: 4 years

Population: 9 out of 25 participants had a partial response.

Arm	Measure	Group	Value (NUMBER)
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	A/A	1 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	G/A	6 participants
Oxaliplatin/Leucovorin/5-FU	Genetic Polymorphisms That May Alter Treatment Outcomes (Partial Response)	G/G	2 participants

Secondary