Fluorouracil, Oxaliplatin, and Leucovorin in Treating Patients With Metastatic Stomach Cancer or Gastroesophageal Junction Cancer

• Sponsor: Vanderbilt-Ingram Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00514020
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 33
• Locations: 5
• Arm: 1
• Duration (Months): 42.1
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as fluorouracil, oxaliplatin, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving fluorouracil together with oxaliplatin and leucovorin works in treating patients with metastatic stomach cancer or gastroesophageal junction cancer.

Condition or Disease	Intervention/Treatment	Phase
Gastric Cancer	Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin; Genetic: gene expression analysis; Genetic: polymorphism analysis; Genetic: protein expression analysis; Other: pharmacological study	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Compare the response rate in patients with "good risk" genotype (TSER*2/2 or TSER2/*3 genotype [low TS expression]) to historical control response rates in non-genotype selected patients.

OUTLINE: This is a multicenter study.

Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.

Available tumor tissue samples are assessed for expression of TS at the mRNA and protein levels. The results are correlated with germline and tumor TSER genotypes as well as response to the study treatment regimen. Polymorphisms in other genes associated with treatment outcome or toxicity are also assessed.

After completion of study treatment, patients are followed periodically for 4 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacogenomically Selected Treatment for Gastric and Gastroesophageal Junction (GEJ) Tumors: A Phase II Study
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Feb 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment

Drug: fluorouracil; Given through a vein over 5 minutes and then continuously over 46 hours on days 1 and 15.; Drug: leucovorin calcium; through a vein over 2 hours on days 1 and 15.; Drug: oxaliplatin; 500 ml D5W through a vein over 2 hours on days 1 and 15.; Genetic: gene expression analysis; Blood collection; Genetic: polymorphism analysis; Blood collection; Genetic: protein expression analysis; Blood collection; Other: pharmacological study; Blood collection

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Each Response in "Good Risk" Genotype (Thymidylate Synthase Promoter Enhancer Region [TSER]*2/*2 or TSER*2/*3 Genotype [Low TS Expression]) [every 8 weeks to progression]

   Per RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions. This is a one-time assessment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed adenocarcinoma of the stomach or gastroesophageal junction

• Metastatic disease

• 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

• No known active brain metastases

• Patients with treated brain metastases are eligible if stable off steroids for at least 30 days

PATIENT CHARACTERISTICS:

• ECOG performance status ≤ 2 (Karnofsky performance status ≥ 60%)

• Life expectancy ≥ 3 months

• WBC ≥ 3,000/μL

• Absolute neutrophil count ≥ 1,500/μL

• Platelets ≥ 100,000/μL

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

• AST or ALT ≤ 2.5 x ULN (< 5 x ULN if known liver metastases)

• Creatinine clearance ≤ 1.5 x ULN

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 21 days after completion of study treatment

• No history of allergic reactions to fluorouracil or oxaliplatin

• No concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

• No prior therapy for metastatic disease

• Prior neoadjuvant or adjuvant therapy is allowed if the disease-free interval has been longer than 6 months

• No other concurrent chemotherapy

• No concurrent combination anti-retroviral therapy for HIV-positive patients

• No concurrent routine prophylaxis with filgrastim (G-CSF)

• No other concurrent antineoplastic agents, including chemotherapy, radiation therapy, or biologic agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	St Louis	Missouri	United States	63110
2	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
3	Vanderbilt-Ingram Cancer Center - Cool Springs	Nashville	Tennessee	United States	37064
4	Vanderbilt-Ingram Cancer Center at Franklin	Nashville	Tennessee	United States	37064
5	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838

Sponsors and Collaborators

• Vanderbilt-Ingram Cancer Center
• National Cancer Institute (NCI)

Investigators

• Study Chair: Laura W. Goff, MD, Vanderbilt-Ingram Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Vanderbilt-Ingram Cancer Center, Find a Clinical Trial

Publications

None provided.

• Responsible Party: Laura W. Goff, MD, Assistant Professor of Medicine; Associate Director, Hematology/Oncology Fellowship Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center
• ClinicalTrials.gov Identifier: NCT00514020
• Other Study ID Numbers: VICC GI 0716; P30CA068485; VU-VICC-GI-0716
• First Posted: Aug 9, 2007
• Last Update Posted: Nov 1, 2012
• Last Verified: Oct 1, 2012

• Keywords provided by Laura W. Goff, MD, Assistant Professor of Medicine; Associate Director, Hematology/Oncology Fellowship Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center: adenocarcinoma of the stomach; stage IV gastric cancer; recurrent gastric cancer
• Additional relevant MeSH terms: Stomach Neoplasms; Leucovorin; Fluorouracil; Oxaliplatin; Calcium; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	This study was conducted from August 2007 to March 2011.
Pre-assignment Detail	Forty-two patients signed consent, 9 of which were found to be ineligible to participate in the study.

Arm/Group Title	5-FU, Leucovorin, Oxaliplatin
Arm/Group Description	Patients who have TSER*2/*2 or TSER*2/*3 genotypes will receive the modified FOLFOX-6 treatment. Patients homozygous for TSER*3 will not be included in study. FOLFOX-6 chemotherapy: oxaliplatin IV in 500 ml D5W over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15. Treatment courses repeat every 2 weeks +/- 3 days (2 treatments per cycle) in the absence of unacceptable toxicity or disease progression. Disease assessments will be performed after 8 weeks (2 cycles) of treatment.
Period Title: Overall Study
STARTED	33
COMPLETED	5
NOT COMPLETED	28

Baseline Characteristics

Arm/Group Title	Oxaliplatin + Leucovorin + 5-Fluorouracil
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours, leucovorin calcium intravenously (IV) over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Overall Participants	33
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 60.6%
>=65 years	13 39.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (1)
Sex: Female, Male (Count of Participants)
Female	13 39.4%
Male	20 60.6%
Region of Enrollment (participants) [Number]
United States	33 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Each Response in "Good Risk" Genotype (Thymidylate Synthase Promoter Enhancer Region [TSER]*2/*2 or TSER*2/*3 Genotype [Low TS Expression])
Description	Per RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions. This is a one-time assessment.
Time Frame	every 8 weeks to progression

Outcome Measure Data

Analysis Population Description

Patients available for measurement of response. All patients who received Oxaliplatin + Leucovorin + 5-Fluorouracil are in the heterozygous "good risk" genotype group. One patient was not evaluable for response.

Arm/Group Title	Oxaliplatin + Leucovorin + 5-Fluorouracil
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours, leucovorin calcium intravenously (IV) over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Measure Participants	24
Complete Response	0 0%
Partial Response	9 27.3%
Progressive Disease	1 3%
Stable Disease	14 42.4%

Adverse Events

Arm/Group Title	Oxaliplatin + Leucovorin + 5-Fluorouracil
Arm/Group Description	Patients receive oxaliplatin IV over 2 hours, leucovorin calcium intravenously (IV) over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
All Cause Mortality
	Oxaliplatin + Leucovorin + 5-Fluorouracil
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Oxaliplatin + Leucovorin + 5-Fluorouracil
	Affected / at Risk (%)	# Events
Total	14/24 (58.3%)
Blood and lymphatic system disorders
INR (international normalized ratio of prothrombin)	1/24 (4.2%)	2
Cardiac disorders
supraventricular and nodal arrhythmia-atrial fibrillation	2/24 (8.3%)	3
Gastrointestinal disorders
constipation	3/24 (12.5%)	6
distension/bloating, abdominal	1/24 (4.2%)	2
dysphagia	3/24 (12.5%)	6
nausea	4/24 (16.7%)	6
pain-abdomen NOS	6/24 (25%)	10
vomiting	3/24 (12.5%)	4
General disorders
fever (in the absence of neutropenia, where neutropenia is defined as ANC < 1.0 x 10e9/L)	1/24 (4.2%)	2
death not associated with CTCAE-disease progression NOS	2/24 (8.3%)	2
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	1/24 (4.2%)	1
AST, SGOT (serum glutamic oxaloacetic transaminase)	1/24 (4.2%)	1
Renal and urinary disorders
obstruction, GU-ureter	1/24 (4.2%)	2
urinary retention	1/24 (4.2%)	1
Skin and subcutaneous tissue disorders
infection with normal ANC or Grade 1 or 2 neutrophils-skin (cellulitis)	1/24 (4.2%)	2
Other (Not Including Serious) Adverse Events
	Oxaliplatin + Leucovorin + 5-Fluorouracil
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
leukocytes (total WBC)	14/24 (58.3%)	32
lymphopenia	9/24 (37.5%)	19
Neutrophils/granulocytes (ANC/AGC)	12/24 (50%)	40
platelets	14/24 (58.3%)	32
Eye disorders
vision/blurred vision	3/24 (12.5%)	3
Gastrointestinal disorders
ascites (non-malignant)	3/24 (12.5%)	4
constipation	7/24 (29.2%)	11
diarrhea	8/24 (33.3%)	14
distension/bloating, abdominal	6/24 (25%)	6
dysphagia	3/24 (12.5%)	3
heartburn/dyspepsia	2/24 (8.3%)	2
mucositis/stomatitis (clinical exam)-oral cavity	4/24 (16.7%)	6
Mucositis/stomatitis (functional/symptomatic)-oral cavity	2/24 (8.3%)	2
nausea	15/24 (62.5%)	22
pain-abdomen NOS	8/24 (33.3%)	16
Taste alteration (dysgeusia)	8/24 (33.3%)	8
vomiting	7/24 (29.2%)	11
General disorders
fatigue	12/24 (50%)	17
pain-other	2/24 (8.3%)	2
Hepatobiliary disorders
bilirubin (hyperbilirubinemia)	2/24 (8.3%)	3
Infections and infestations
fever in the absence of neutropenia, where neutropenia is defined as ANC < 1.0 x 12e9/L	2/24 (8.3%)	2
infection with normal ANC or Grade 1 or 2 neutrophils-abdomen NOS	2/24 (8.3%)	2
Investigations
alkaline phosphatase	10/24 (41.7%)	13
ALT/SGPT (serum glutamine pyruvic transminase)	11/24 (45.8%)	15
AST, SGOT (serum glutamine oxaloacetic transminase)	11/24 (45.8%)	13
creatine	2/24 (8.3%)	3
hemoglobin	22/24 (91.7%)	33
metabolic/laboratory-other	2/24 (8.3%)	2
weight loss	2/24 (8.3%)	2
Metabolism and nutrition disorders
albumin, serum-low	17/24 (70.8%)	29
anorexia	8/24 (33.3%)	8
calcium, serum-low-hypocalcemia	10/24 (41.7%)	14
glucose, serum-high-hyperglycemia	11/24 (45.8%)	21
potassium, serum-low (hypokalemia)	6/24 (25%)	10
sodium, serum-low (hyponatremia)	4/24 (16.7%)	8
Musculoskeletal and connective tissue disorders
edema-limb	3/24 (12.5%)	3
Pain-extremity-limb	2/24 (8.3%)	2
Nervous system disorders
dizziness	2/24 (8.3%)	2
neuropathy - sensory	14/24 (58.3%)	39
Psychiatric disorders
insomnia	3/24 (12.5%)	4
mood alteration-anxiety	2/24 (8.3%)	2
mood alteration-depression	2/24 (8.3%)	2
Skin and subcutaneous tissue disorders
dermatology/skin-other	2/24 (8.3%)	3
rash-hand-foot skin reaction	2/24 (8.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.