Pilot Study of Correlation Between Molecular Phenotype and Response to Two Independent Treatment Regimens, Carboplatin and Paclitaxel vs. 5-Fluorouracil and Oxaliplatin Chemotherapy in Patients With Localized Esophageal Adenocarcinoma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Relative Expression Differences in Individual Genes and Gene Profiles Between Patients Responding and Not Responding to Treatment, as Assessed by (18F) FDG-PET
研究概览
简要总结
This randomized pilot phase II trial studies how well molecular phenotyping works in predicting response in patients with stage IB-III esophageal cancer who are receiving carboplatin and paclitaxel or oxaliplatin, leucovorin calcium, and fluorouracil. Studying the genes in a patients tumor cells before and after chemotherapy may help in understanding if there are specific features of the tumor cells that make a person more or less likely to respond to treatment and how these features may be affected by treatment.
详细描述
PRIMARY OBJECTIVES:
I. To evaluate gene and micro ribonucleic acid (miRNA) expression levels in patients with esophageal adenocarcinoma prior to receiving chemotherapy and identify relative expression differences between patients responding and not responding to treatment with carboplatin and paclitaxel or 5-fluorouracil (fluorouracil) and oxaliplatin as measured by fluorodeoxyglucose F-18 ([18F] FDG)-positron emission tomography (PET).
SECONDARY OBJECTIVES:
I. To evaluate the impact of treatment on expression patterns of both genes and miRNAs in patients with esophageal adenocarcinoma following treatment with either carboplatin and paclitaxel or 5-fluorouracil and oxaliplatin, and identify expression patterns associated with treatment response and resistance as assessed by (18F) FDG-PET.
II. To evaluate the expression patterns of genes and miRNAs in patients with esophageal adenocarcinoma prior to and following a full neoadjuvant combined-modality treatment program with either carboplatin and paclitaxel or 5-fluorouracil and oxaliplatin chemotherapy plus radiation, and identify relative expression differences between patients achieving a pathologic complete response and patients not achieving a pathologic complete response.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically or cytologically confirmed localized (T1N1-3M0 or T2-4NanyM0, stage IB-III) Siewert type 1 or type 2 esophageal adenocarcinoma that is amenable to surgical resection as determined by a thoracic surgeon and for which all disease (primary tumor and involved lymph nodes) can be treated with radiation, as determined by a radiation oncologist
- •Patients may not have received any prior chemotherapy, biologic therapy or radiation therapy for management of their disease; chemotherapy or biologic therapy administered for treatment of another primary malignancy are permitted if treatment was greater than 5 years ago
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- •Patients must have a life expectancy of > 3 months, in the opinion of and as documented by the investigator
- •Hemoglobin >= 10.0 g/dl
- •Absolute neutrophil count >= 1,500/mcL
- •Platelet count >= 100,000/mcL
- •Total bilirubin within normal institutional limits
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional upper limit of normal
- •Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
- •Serum creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (as calculated by Cockcroft-Gault)
- •Patients must have an avid primary tumor with an standardized uptake value (SUV) of >= 5 on baseline (18F) FDG-PET/computed tomography (CT) imaging
- •Men must agree to use adequate contraception (double barrier method of birth control or abstinence) 1 week prior to study entry, for the duration of study participation and for 1 month after completing combined modality treatment with chemotherapy and radiation; should a male patient's female partner become pregnant or suspect that she is pregnant while her partner is participating in this study, the treating physician should be informed immediately
- •Patients must have the ability to understand and the willingness to sign a written informed consent document
- •This study will be limited to enrollment of Caucasian males only
排除标准
- •Patients who are receiving any chemotherapy, biologic therapy, radiation therapy or any investigational agent
- •Patients with metastatic disease
- •Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to platinums, taxanes or fluoropyrimidines
- •Patients who have previously received radiation therapy to the chest or abdomen such that there would be overlap between the previous and current radiation field
- •Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Patients with human immunodeficiency virus (HIV) whom are not receiving antiretroviral therapy
- •Patients with another malignancy within the past 5 years
研究组 & 干预措施
Arm I (paclitaxel, carboplatin, radiation therapy, surgery)
INDUCTION: Patients receive chemotherapy with carboplatin and paclitaxel. Patients receive carboplatin (AUC=2) and paclitaxel (90 mg/m2) intravenously on days 1 and 8 of a 21 day treatment cycle for two cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive carboplatin (AUC=2) and paclitaxel (50 mg/m2) intravenously once weekly for five weeks throughout the duration of their radiation which is daily (Monday through Friday).
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Paclitaxel (Drug)
Arm I (paclitaxel, carboplatin, radiation therapy, surgery)
INDUCTION: Patients receive chemotherapy with carboplatin and paclitaxel. Patients receive carboplatin (AUC=2) and paclitaxel (90 mg/m2) intravenously on days 1 and 8 of a 21 day treatment cycle for two cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive carboplatin (AUC=2) and paclitaxel (50 mg/m2) intravenously once weekly for five weeks throughout the duration of their radiation which is daily (Monday through Friday).
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Carboplatin (Drug)
Arm I (paclitaxel, carboplatin, radiation therapy, surgery)
INDUCTION: Patients receive chemotherapy with carboplatin and paclitaxel. Patients receive carboplatin (AUC=2) and paclitaxel (90 mg/m2) intravenously on days 1 and 8 of a 21 day treatment cycle for two cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive carboplatin (AUC=2) and paclitaxel (50 mg/m2) intravenously once weekly for five weeks throughout the duration of their radiation which is daily (Monday through Friday).
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Radiation Therapy (Radiation)
Arm I (paclitaxel, carboplatin, radiation therapy, surgery)
INDUCTION: Patients receive chemotherapy with carboplatin and paclitaxel. Patients receive carboplatin (AUC=2) and paclitaxel (90 mg/m2) intravenously on days 1 and 8 of a 21 day treatment cycle for two cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive carboplatin (AUC=2) and paclitaxel (50 mg/m2) intravenously once weekly for five weeks throughout the duration of their radiation which is daily (Monday through Friday).
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Therapeutic Conventional Surgery (Procedure)
Arm I (paclitaxel, carboplatin, radiation therapy, surgery)
INDUCTION: Patients receive chemotherapy with carboplatin and paclitaxel. Patients receive carboplatin (AUC=2) and paclitaxel (90 mg/m2) intravenously on days 1 and 8 of a 21 day treatment cycle for two cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive carboplatin (AUC=2) and paclitaxel (50 mg/m2) intravenously once weekly for five weeks throughout the duration of their radiation which is daily (Monday through Friday).
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (combination chemotherapy, radiation therapy, surgery)
INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks.
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Oxaliplatin (Drug)
Arm II (combination chemotherapy, radiation therapy, surgery)
INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks.
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Leucovorin Calcium (Drug)
Arm II (combination chemotherapy, radiation therapy, surgery)
INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks.
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Fluorouracil (Drug)
Arm II (combination chemotherapy, radiation therapy, surgery)
INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks.
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Radiation Therapy (Radiation)
Arm II (combination chemotherapy, radiation therapy, surgery)
INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks.
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Therapeutic Conventional Surgery (Procedure)
Arm II (combination chemotherapy, radiation therapy, surgery)
INDUCTION: Patients receive mFOLFOX6 where they get oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 400 mg/m2 IV on day 1, 5-FU 400 mg/m2 IV on day 1 and then 5FU at 2400 mg/m2 IV to be administered over a 46 hour period. This is repeated every 2 weeks for 3 cycles (total of 6 weeks).
CHEMORADIATION THERAPY: Patients receive oxaliplatin 85 mg/m2 IV on day 1 every 2 weeks for a total of 3 cycles (6 weeks) as well as 5FU 300 mg/m2/day over 96 hours via continuous infusion each week of radiation for a total of 6 weeks.
SURGERY: Approximately 4-10 weeks after completion of chemoradiation therapy, patients undergo esophagectomy at the discretion of the treating team.
干预措施: Laboratory Biomarker Analysis (Other)
结局指标
主要结局
Relative Expression Differences in Individual Genes and Gene Profiles Between Patients Responding and Not Responding to Treatment, as Assessed by (18F) FDG-PET
时间窗: Baseline
Baseline gene profiles will be compared for 10 (18F) FDG-PET responders vs. 15 (18F) FDG-PET non-responders per treatment regimen using a t-test and p-values will be corrected for multiple comparisons by calculating the false discovery rate (FDR) p-value (filtering on a FDR p-value \< 0.05). Top genes identified will be tested in combination for their sensitivity and specificity using logistic regression models.
Relative Expression Differences in Individual microRNAs and microRNA Profiles Between Patients Responding and Not Responding to Treatment, Assessed by (18F) FDG-PET
时间窗: Baseline
Baseline microRNA profiles will be compared for 10 (18F) FDG-PET responders vs. 15 (18F) FDG-PET non-responders per treatment regimen using a t-test and p-values will be corrected for multiple comparisons by calculating the FDR p-value (filtering on a FDR p-value \< 0.05). Top microRNAs identified will be tested in combination for their sensitivity and specificity using logistic regression models.
Biological Pathway Perturbation Upon Exposure to Chemotherapy
时间窗: Up to 6 weeks
Predefined signatures of biological pathway activities will be evaluated in order to identify pathway perturbation upon exposure to chemotherapy. Significant pathway modulations upon brief exposure will then be evaluated for association with clinical response using non-parametric tests such as the Wilcoxon signed-rank test. In all cases, statistical correction to account for multiple hypothesis testing will be employed and pathways with a false discovery rate of 10% or lower will be considered as significant.
次要结局
- Relative Expression Differences Between Baseline and Post-induction Chemotherapy Specimens of Individual Genes and Gene Expression Profiles(Baseline to post-induction (36-43 days))
- Relative Expression Differences Between Baseline and Post-induction Chemotherapy Specimens of Individual microRNAs and microRNA Profiles(Baseline to post-induction (36-43 days))
- Relative Expression Differences in Baseline Individual Genes and Gene Expression Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment(Baseline)
- Relative Expression Differences in Baseline Individual microRNAs and microRNA Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment(Baseline)
- Relative Expression Differences Between Baseline and Post-induction Gene Expression Levels/Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment(Baseline to post-induction (36-43 days))
- Relative Expression Differences Between Baseline and Post-induction microRNA Levels/Profiles Between Patients Achieving and Not Achieving a Pathologic Complete Response Following Treatment(Baseline to post-induction (36-43 days))
- Occurrence of Grade 3 or 4 Toxicity Per the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.0(Up to 30 days after the end of treatment)