Adenocarcinoma of the Gastroesophageal Junction, Esophageal Undifferentiated Carcinoma, Gastric Adenocarcinoma, Gastric Squamous Cell Carcinoma, Recurrent Esophageal Adenocarcinoma, Recurrent Esophageal Squamous Cell Carcinoma, Recurrent Gastric Carcinoma, Stage IIIB Esophageal Adenocarcinoma, Stage IIIB Esophageal Squamous Cell Carcinoma, Stage IIIB Gastric Cancer, Stage IIIC Esophageal Adenocarcinoma, Stage IIIC Esophageal Squamous Cell Carcinoma, Stage IIIC Gastric Cancer, Stage IV Esophageal Adenocarcinoma, Stage IV Esophageal Squamous Cell Carcinoma, Stage IV Gastric Cancer, Undifferentiated Gastric Carcinoma
Conditions
Brief summary
This phase II trial studies how well pralatrexate and oxaliplatin work in treating patients with esophageal, stomach, or gastroesophageal junction cancer that cannot be removed by surgery or has spread from the primary site (place where it started) to other places in the body. Pralatrexate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pralatrexate with oxaliplatin may be an effective treatment for esophageal, stomach, or gastroesophageal junction cancer.
Detailed description
PRIMARY OBJECTIVES: I. To determine the overall response rate in patients with advanced esophago-gastric cancer (EGC) to combination pralatrexate and oxaliplatin. SECONDARY OBJECTIVES: I. To examine the toxicity and tolerability of this regimen. II. To determine the time-to-progression and overall survival using this regimen. III. To examine whether functionally relevant polymorphisms of genes of the folate metabolism pathway correlate with efficacy and toxicity of pralatrexate. IV. To examine whether response to pralatrexate can be predicted by micro-ribonucleic acid (microRNA) expression profiling of the epithelial component of the tumor. OUTLINE: Patients receive pralatrexate intravenously (IV) over 3-5 minutes and oxaliplatin IV over 2 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Oxaliplatin will be discontinued after 12 courses. After completion of study treatment, patients are followed up for 30 days and then periodically thereafter for up to 5 years.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGOxaliplatin
Given IV
DRUGPralatrexate
Given IV
Sponsors
National Cancer Institute (NCI)
National Comprehensive Cancer Network
Roswell Park Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed carcinoma of the esophagus, stomach or gastro-esophageal junction that is metastatic, or locally advanced and inoperable for cure; histological sub-types permitted include adenocarcinoma, squamous-cell carcinoma, or undifferentiated carcinoma; small-cell carcinoma variant is not eligible * No previous systemic therapy for metastatic or recurrent disease; therapy (chemotherapy, radiotherapy, or both) administered in the neo-adjuvant, adjuvant, or definitive setting for previously localized disease is permitted, provided it was completed more than 6 months prior to enrollment; palliative radiotherapy is permitted provided it is completed \>= 3 weeks prior to study therapy initiation * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Life expectancy \>= 12 weeks * Hemoglobin \>= 9 g/dl * Absolute neutrophil count \>= 1500/mm\^3 * Platelet count \>= 100,000/mm\^3 * Serum creatinine =\< institutional upper limit normal (ULN) * Bilirubin =\< 1.5 x ULN * Transaminases =\< 3 x ULN; for documented liver metastases, transaminases up to 5 x ULN is permitted * No evidence of \>= grade 2 peripheral neuropathy * Patients with reproductive potential must be willing to use an adequate contraceptive method (e.g., abstinence, intrauterine device, oral contraceptives, barrier device with spermicide or surgical sterilization) during treatment and for three months after completing treatment; a negative pregnancy test is required for women of child-bearing potential; nursing women are ineligible * Written, informed consent
Exclusion criteria
* Hypersensitivity to platinum compounds * Uncontrolled inter-current illness including but not limited to active infection, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements * Presence of brain metastases * Patients with third-space (pleural, peritoneal) fluid not controllable with usual drainage methods are not eligible * History of second primary malignancy within 3 years prior to enrollment, except for in-situ cervix carcinoma or non-melanoma skin cancer * Undergone an allogeneic stem cell transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 5 years | Overall response rate to combination pralatrexate and oxaliplatin as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Objective responses will be confirmed 4 weeks after first documentation of response. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Adverse Event | Up to 30 days after the last dose of study drug(s) | Number of participants with an adverse event. Please refer to the adverse event reporting for more detail. Incidence of toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |
| Overall Survival (OS) | From the date of study enrollment to the time of death from any cause, assessed up to 5 years | Estimated using the Kaplan-Meier method and proportional hazards models. |
| Time to Progression (TTP) | From the date of study enrollment to the first observation of progressive disease, assessed up to 5 years | Estimated using the Kaplan-Meier method and proportional hazards models. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) for SNP ATIC/AICART - s10932606 Genotypes | From the date of study enrollment up to 5 years | Kaplan-Meier estimates of median survival time for each genotype |
| MicroRNA Expression - miR-215-5p | Baseline | Mean microRNAs expression of mi-215-5p in tumor tissues of responders and non-responders using a microfabricated device called a gene chip. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Pralatrexate, Oxaliplatin) Patients receive pralatrexate IV over 3-5 minutes and oxaliplatin IV over 2 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Oxaliplatin will be discontinued after 12 courses.
Laboratory Biomarker Analysis: Correlative studies
Oxaliplatin: Given IV
Pralatrexate: Given IV | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | Treatment (Pralatrexate, Oxaliplatin) |
|---|---|
| Age, Continuous | 64.7 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 35 / 35 |
| serious Total, serious adverse events | 10 / 35 |
Outcome results
Primary
Overall Response Rate
Overall response rate to combination pralatrexate and oxaliplatin as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Objective responses will be confirmed 4 weeks after first documentation of response. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 5 years
Population: All Cohort -1 treated and eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pralatrexate, Oxaliplatin) | Overall Response Rate | 26 percentage of participants |
Secondary
Number of Participants With an Adverse Event
Number of participants with an adverse event. Please refer to the adverse event reporting for more detail. Incidence of toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: Up to 30 days after the last dose of study drug(s)
Population: All treated and eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Pralatrexate, Oxaliplatin) | Number of Participants With an Adverse Event | 35 participants |
Secondary
Overall Survival (OS)
Estimated using the Kaplan-Meier method and proportional hazards models.
Time frame: From the date of study enrollment to the time of death from any cause, assessed up to 5 years
Population: All treated and eligible patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pralatrexate, Oxaliplatin) | Overall Survival (OS) | 7.2 months |
Secondary
Time to Progression (TTP)
Estimated using the Kaplan-Meier method and proportional hazards models.
Time frame: From the date of study enrollment to the first observation of progressive disease, assessed up to 5 years
Population: All treated and eligible patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pralatrexate, Oxaliplatin) | Time to Progression (TTP) | 5.1 months |
Other Pre-specified
MicroRNA Expression - miR-215-5p
Mean microRNAs expression of mi-215-5p in tumor tissues of responders and non-responders using a microfabricated device called a gene chip.
Time frame: Baseline
Population: All treated participants that had enough tissue to perform microdissection to collect epithelial cells for subsequent microRNA profiling.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment (Pralatrexate, Oxaliplatin) | MicroRNA Expression - miR-215-5p | Responders: CR+PR | 6.6 Arbitrary fluorescent intensity |
| Treatment (Pralatrexate, Oxaliplatin) | MicroRNA Expression - miR-215-5p | Non responders: stable disease/progression | 5.6 Arbitrary fluorescent intensity |
Comparison: Comparison is CR+PR vs stable disease/progressionp-value: 0.58595% CI: [0.78, 1.38]t-test, 2 sided
Other Pre-specified
Overall Survival (OS) for SNP ATIC/AICART - s10932606 Genotypes
Kaplan-Meier estimates of median survival time for each genotype
Time frame: From the date of study enrollment up to 5 years
Population: All treated and eligible patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (Pralatrexate, Oxaliplatin) | Overall Survival (OS) for SNP ATIC/AICART - s10932606 Genotypes | C | 10.22 months |
| Treatment (Pralatrexate, Oxaliplatin) | Overall Survival (OS) for SNP ATIC/AICART - s10932606 Genotypes | T | 18.71 months |
| Treatment (Pralatrexate, Oxaliplatin) | Overall Survival (OS) for SNP ATIC/AICART - s10932606 Genotypes | TC | 4.63 months |