S1201: Combination Chemo for Patients W/Advanced or Metastatic Esophageal, Gastric, or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, irinotecan hydrochloride, and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy is more effective in treating tumor cells. PURPOSE: This randomized phase II trial studies how well oxaliplatin, leucovorin calcium, and fluorouracil work compared to irinotecan hydrochloride and docetaxel in treating patients with esophageal cancer, gastric cancer, or gastroesophageal junction cancer.

Detailed Description
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OBJECTIVES: To assess progression-free survival of high-excision repair cross-complementing 1(ERCC1) patients with advanced or metastatic cancer of the esophagus, stomach, or gastroesophageal junction (GEJ) treated with FOLFOX comprising oxaliplatin, leucovorin calcium, and fluorouracil compared to those treated with irinotecan hydrochloride plus docetaxel. To assess progression-free survival of low-ERCC1 patients with advanced or metastatic cancer of the esophagus, stomach, or GEJ treated with FOLFOX compared to those treated with irinotecan hydrochloride plus docetaxel. To assess progression-free survival of low-ERCC1 patients with advanced or metastatic cancer of the esophagus, stomach, or GEJ treated with FOLFOX compared to high-ERCC1 patients treated with FOLFOX. To assess overall survival of and toxicities in each of the two treatment arms in this group of patients. To assess the response probability (confirmed and unconfirmed, complete and partial responses) in the subset of patients with measurable disease in each of the two treatment arms. To explore whether there is evidence of interaction between treatment arm and ERCC1 expression in this group of patients. (Exploratory) To bank tissue and blood for future translational medicine studies; a) To explore the relationship of ERCC-1 and ERCC-2 single nucleotide polymorphism (SNP) genotypes with clinical outcome in these patients; and b) To explore the association between germline variations in these SNPs and ERCC-1 mRNA expression in these patients. (Exploratory) OUTLINE: This is a multicenter study. Patients are stratified according to ERCC1 expression (high [≥ 1.7] vs low [< 1.7]), and disease site (esophageal vs gastric/gastroesophageal junction). Patients are randomized to 1 of 2 treatment arms. Arm I (FOLFOX): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive irinotecan hydrochloride IV over 90 minutes and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and tumor tissue samples may be collected for ERCC1 expression analysis and future research studies. After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Official Title
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A Randomized Phase II Pilot Study Prospectively Evaluating Treatment for Patients Based on ERCC1(Excision Repair Cross-Complementing 1) for Advanced/Metastatic Esophageal, Gastric or Gastroesophageal Junction (GEJ) Cancer

Conditions
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Adenocarcinoma of the Gastroesophageal Junction, Esophageal Cancer, Gastric Cancer

Intervention / Treatment
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* Drug: FOLFOX regimen
* Drug: docetaxel
* Drug: fluorouracil
* Drug: irinotecan hydrochloride
* Drug: leucovorin calcium
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Patients must have unresectable advanced or metastatic histologically or cytologically confirmed adenocarcinoma of the esophagus, stomach, or gastroesophageal junction (GEJ) Patients must not have received treatment for metastatic or unresectable disease Patients must not have brain metastases Patients must have measurable and/or non-measurable disease Patients who have had HER-2 expression testing prior to patient consent to this study must be HER-2 negative; if HER-2 expression has not been tested prior to patient consent to this study, a second specimen must be submitted for HER-2 expression; if the specimen is HER-2 positive (or if HER-2 could not be evaluated), the patient will not be randomized Patients must have completed any prior neoadjuvant and adjuvant therapy for resectable disease at least 180 days prior to registration PATIENT CHARACTERISTICS: Zubrod performance status of 0-1 Hemoglobin ≥ 9 g/dL Absolute neutrophil count (ANC) ≥ 1,500/mcL Platelets ≥ 100,000/mcL Total bilirubin ≤ 1.5 mg/dL regardless of whether patients have liver involvement secondary to tumor AST and ALT both ≤ 3 times institutional upper limit of normal (IULN) unless the liver is involved with tumor, in which case both AST and ALT must be ≤ 5 times IULN Serum creatinine < 1.5 mg/dL within 28 days prior to registration AND/OR calculated creatinine clearance > 60 mL/min Patients must not have motor or sensory neuropathy > Grade 1 using CTCAE version 4.0 Patients must not be pregnant or nursing; women and men of reproductive potential must have agreed to use an effective contraceptive method No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for five years PRIOR CONCURRENT THERAPY: See Disease Characteristics All palliative radiation therapy alone must be completed at least 14 days prior to registration Patient must have no plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or any other type of therapy for treatment of cancer while on this protocol treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>FOLFOX regimen: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Drug: FOLFOX regimen<br>* Given IV. Fluorouracil, oxaliplatin, & leucovorin calcium.<br>Drug: fluorouracil<br>* 400 mg/m^2, IV bolus on Day 1 of each 14 day cycle; 2400 mg/m^2 IV over 46-48 hours on Days 1-2 of each 14 day cycle.<br>* Other names: NSC-19893;Drug: leucovorin calcium<br>* 400 mg/m^2, IV over 2 hours on Day 1 of every 14 day cycle.<br>* Other names: NSC-3590;Drug: oxaliplatin<br>* 85 mg/m^2, IV over 2 hours on Day 1 of every 14 day cycle.<br>* Other names: NSC-266046;|
| Experimental: Arm II<br>Patients receive irinotecan hydrochloride IV over 90 minutes and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: docetaxel<br>* 30 mg/m^2, IV over 30 minutes on Day 1,8 of each 21 day cycle.<br>* Other names: NSC-628503;Drug: irinotecan hydrochloride<br>* 65 mg/m^2, IV over 90 minutes on Days 1 & 8 of every 21 day cycle.<br>* Other names: NSC-616348;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) in High-ERCC1 Patients | Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first. | Up to 3 years after registration | 
| PFS in Low-ERCC1 Participants | Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first. | Up to 3 years after registration | 
| Overall Survival (OS) | OS is the length of time between protocol registration and patient death | Up to 3 years after registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR (complete response, unconfirmed complete response, partial response, unconfirmed partial response) in patients with measurable disease were assessed in each arm and compared between arms using Chi-squared test. 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. | Up to 3 years after registration | 
| PFS Variation by ERCC1 | Progression-free survival is the length of time between protocol registration and disease progression or death, whichever occurs first. Participants were divided into subgroups according to ERCC1 quartiles to assess whether the differences in PFS between the two treatment arms varied by ERCC1 levels. | up to 3 years after registration | 
| Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Duration of treatment and follow up until death or 3 years post registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent esophageal cancer, stage IV esophageal cancer, recurrent gastric cancer, stage IV gastric cancer, adenocarcinoma of the gastroesophageal junction, stage IIIB gastric cancer, stage IIIC gastric cancer, stage IIIB esophageal cancer, stage IIIC esophageal cancer, adenocarcinoma of the esophagus, adenocarcinoma of the stomach