Irinotecan and Cisplatin in Treating Patients Who Are Undergoing Surgery For Locally Advanced Cancer of the Stomach or Gastroesophageal Junction

Study Overview
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Brief Summary
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This phase II trial is studying how well giving irinotecan together with cisplatin works in treating patients who are undergoing surgical resection for locally advanced cancer of the stomach or gastroesophageal junction. Drugs used in chemotherapy, such as irinotecan and cisplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one chemotherapy drug and giving them before surgery may shrink the tumor so that it can be removed during surgery.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the correlation of fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging early in the preoperative treatment program of locally advanced gastric cancer with histologic response assessment and patient outcome, defined as overall and progression-free survival. SECONDARY OBJECTIVES: I. To evaluate the efficacy and safety of preoperative chemotherapy with irinotecan and cisplatin in the treatment of locally advanced gastric cancer. II. To examine the biology of locally advanced gastric cancer and the response to chemotherapy by DNA microarray technology and by histopathology. III. To obtain preliminary data on biodistribution, dosimetry and explore the potential clinical usefulness of fluorodeoxythymidine (FLT) PET in patients with locally advanced gastric cancer undergoing a novel combination neoadjuvant chemotherapy. OUTLINE: This is an open-label, nonrandomized, multicenter study. Neoadjuvant chemotherapy: Patients receive cisplatin intravenously (IV) over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection. Patients undergo fluorodeoxyglucose FDG-PET/CT at baseline. Some patients undergo additional FDG-PET/CT scans in weeks 3 and 6. Approximately 5 patients undergo fluorothymidine FLT-PET/CT at baseline, during week 3, and/or before surgical resection. Patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Official Title
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An Evaluation of Preoperative Chemotherapy With Irinotecan and Cisplatin for Advanced, But Resectable Gastric Cancer: A Coordinated Multidisciplinary, Multicenter Study Linking Functional Imaging, Genomic Expression Profiles and Histopathology

Conditions
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Gastric Adenocarcinoma, Stage II Gastric Cancer, Stage III Gastric Cancer, Stage IV Gastric Cancer

Intervention / Treatment
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* Drug: Cisplatin
* Procedure: Computed Tomography
* Radiation: Fludeoxyglucose F-18
* Other: Fluorothymidine F-18
* Drug: Irinotecan Hydrochloride
* Procedure: Positron Emission Tomography
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have microscopically confirmed adenocarcinoma of the stomach or gastroesophageal (GE) junction with material reviewed by the Department of Pathology of the participating Institution; tumors involving the GE junction must have the bulk of their disease in the stomach; tumors of the distal esophagus that extend less than 2cm into the stomach are ineligible for this study; using the Siewert's classification for the GE junction, tumors designated as Types II and III are indeed considered eligible for this clinical trial All patients must have localized cancer potentially curable by surgery; the tumor stage should be Tany N+ M0 or T3-T4 Nany M0, by staging that includes a computed tomography (CT) scan and either laparoscopy-assisted pancreatobiliary (LAP) or endoscopic ultrasound (EUS); patients with T1-2N0M0 tumors, confirmed by LAP (good risk) are ineligible; any sites of suspected M1 disease by these criteria must be proven to be M0 prior to entrance into a neoadjuvant trial Patients must have a Karnofsky Performance Status >= 60% (Eastern Cooperative Oncology Group [ECOG] =< 2) and be able to tolerate the proposed surgical procedure and chemotherapy regimen Patients may not have received prior chemotherapy or radiation for this disease Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 Platelets >= 100,000/mm^3 Serum creatinine =< 1.5 mg/dL Total serum bilirubin =< 1.5 mg/dL Patients must have signed informed consent indicating that they are aware of the investigational nature of the study and that participation is voluntary No clinically significant auditory impairment No clinically significant peripheral neuropathy New York Heart Association (NYHA) class I-II Patients must not have a prior history of cancer within the last five years except for non-melanoma skin cancer, non-metastatic prostate cancer or carcinoma in situ of the uterine cervix Exclusion Criteria: Any metastatic disease NYHA Class III or IV heart disease; history of active angina or myocardial infarction within 6 months; history of significant ventricular arrhythmia requiring medication with antiarrhythmics or a history of a clinically significant conduction system abnormality Pregnant or lactating women are ineligible; fertile men and women, unless using effective contraception, are ineligible; a pregnancy test will be performed on sexually active women of childbearing potential prior to entry into the study; treatment may not begin until the results of the pregnancy test are ascertained Serious intercurrent infections, or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this therapy Grade 2 or greater pre-existing peripheral neuropathy Psychiatric disorders rendering patients incapable of complying with the requirements of the protocol Any concurrent active malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer or carcinoma-in-situ of the uterine cervix; patients with previous malignancies but without evidence of disease for > 5 years will be allowed to enter the trial Clinically significant hearing loss

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (preoperative chemotherapy)<br>Neoadjuvant chemotherapy: Patients receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1, 8, 22, and 29. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Surgery: Within 4 weeks after completion of neoadjuvant chemotherapy, patients undergo radical subtotal or total gastrectomy with lymph node dissection. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo FDG and FLT PET/CT<br>* Other names: tomography;Radiation: Fludeoxyglucose F-18<br>* Undergo FDG-PET/CT<br>* Other names: Fluorodeoxyglucose F18;Other: Fluorothymidine F-18<br>* Undergo FLT-PET/CT<br>* Other names: Fluorothymidine F 18;Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;Procedure: Positron Emission Tomography<br>* Undergo FDG and FLT PET/CT<br>* Other names: proton magnetic resonance spectroscopic imaging;Procedure: Therapeutic Conventional Surgery<br>* Undergo radical subtotal or total gastrectomy with lymph node dissection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological Response Determined by FDG Uptake Correlates | The primary objective was to demonstrate that a decrease in FDG-SUV discriminates treatment response. Response was defined pathologically based on microscopic inspection for residual cancer cells and fibrosis. Using a two sample t-test, we would be able to adequately test that the decrease in SUV early in the treatment plan is significantly different between responders and non responders. Data adjudication was invalid, and needs to be re-adjudicated Non-Responder= Tumor Regression Grade 3 or higher Responder=Tumor Regression Grade 1 (CR) or Grade 2 (PR) | Day 15 |