Irinotecan, Cisplatin, and Bevacizumab in Treating Patients With Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying how well giving irinotecan and cisplatin together with bevacizumab works in treating patients with unresectable or metastatic gastric (stomach) or gastroesophageal junction adenocarcinoma (cancer). 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. Monoclonal antibodies such as bevacizumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Giving chemotherapy together with a monoclonal antibody may kill more tumor cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Determine the efficacy of irinotecan, cisplatin, and bevacizumab, in terms of time to progression, in patients with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. SECONDARY OBJECTIVES: I. Determine other measures of efficacy, including response rate and median and 1-year survival, in patients treated with this regimen. II. Determine the toxicity of this regimen in these patients. III. Correlate CT perfusion imaging results with the efficacy of this regimen, in terms of time to progression, objective response, and survival, in these patients. IV. Determine the feasibility of serial serum proteomic assays in predicting response to therapy, in terms of time to progression, objective response, and survival, in patients treated with this regimen. V. To bank paraffin stored tumor biopsy material for future planned immunohistochemistry studies to correlate with sensitivity to bevacizumab based combination chemotherapy. OUTLINE: This is an open-label, non-randomized, multicenter study. Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year.

Official Title
-----------------
A Multicenter, Open-Label, Phase II Study of Irinotecan, Cisplatin, and Bevacizumab in Patients With Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Conditions
-----------------
Adenocarcinoma of the Gastroesophageal Junction, Diffuse Adenocarcinoma of the Stomach, Intestinal Adenocarcinoma of the Stomach, Mixed Adenocarcinoma of the Stomach, Recurrent Gastric Cancer, Stage IIIA Gastric Cancer, Stage IIIB Gastric Cancer, Stage IIIC Gastric Cancer, Stage IV Gastric Cancer

Intervention / Treatment
-----------------
* Drug: irinotecan hydrochloride
* Biological: bevacizumab
* Drug: cisplatin
* Procedure: computed tomography
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed gastric or gastroesophageal junction (GEJ) adenocarcinoma Metastatic or unresectable disease Siewert's classification I, II, or III No ulcerated, non-healing tumors or tumors that have developed a malignant fistula No esophageal tumors No known or active brain metastases Performance status - Karnofsky 60-100% Performance status - ECOG 0-2 Neutrophil count >= 1,500/mm^3 Platelet count >= 75,000/mm^3 No bleeding diathesis or coagulopathy Bilirubin =< 1.5 mg/dL AST and ALT =< 3 times upper limit of normal (ULN) (5 times ULN if liver metastases are present) PT (INR) =< 1.5 PTT =< 3 seconds above ULN Creatinine =< 1.5 mg/dL Proteinuria < 1+ Protein < 500 mg/24-hour urine collection No acute ischemia or significant conduction abnormality by EKG No clinically significant cardiovascular disease No uncontrolled hypertension (blood pressure > 160/90 mm Hg on medication) No myocardial infarction within the past 6 months No unstable angina within the past 6 months No transient ischemic attack within the past 6 months No cerebrovascular accident within the past 6 months No other arterial thromboembolic event within the past 6 months No New York Heart Association class II-IV congestive heart failure No serious cardiac dysrhythmia requiring medication No peripheral vascular disease (grade II or greater) No history of stroke No CNS disease within the past 5 years (e.g., uncontrolled seizures) No other concurrent uncontrolled illness No ongoing or active infection requiring parental antibiotics on Day 0 of study No serious, non-healing wound No serious wound healing by secondary intention No ulcer No bone fracture No psychiatric illness or social situation that would preclude study compliance No significant traumatic injury within the past 28 days No other neoplastic disease within the past 3 years except basal cell skin cancer, carcinoma in situ of the cervix, or nonmetastatic prostate cancer No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No other medical condition that would preclude study participation Not pregnant or nursing No nursing during and for 4 months after study participation Negative pregnancy test Fertile patients must use effective contraception during and for 4 months after study participation More than 8 weeks since prior immunotherapy and recovered No other concurrent biologic or immunologic agents No other concurrent bevacizumab No prior chemotherapy for metastatic disease No prior cisplatin or irinotecan Prior neoadjuvant and/or adjuvant chemotherapy or chemoradiotherapy allowed More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered No other concurrent chemotherapy More than 3 weeks since prior radiotherapy and recovered No concurrent radiotherapy More than 28 days since prior major surgical procedure or open biopsy More than 7 days since prior fine needle aspirations or core biopsies No concurrent major surgery No other concurrent investigational agents No other concurrent anticancer therapy No concurrent chronic daily aspirin (> 325 mg/day) No concurrent nonsteroidal anti-inflammatory medications that would inhibit platelet function at doses used to treat chronic inflammatory diseases Full-dose anticoagulants allowed, provided the following criteria are met: INR in range (i.e., 2-3) while on a stable dose of warfarin or low molecular weight heparin No active bleeding or pathologic condition that would confer a high risk of bleeding (e.g., tumor involving major blood vessels or known varices) No concurrent thrombolytic agents No concurrent vitamins, antioxidants, herbal preparations, or supplements Single tablet multivitamin allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bevacizumab, cisplatin, irinotecan)<br>Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive cisplatin IV over 30 minutes followed by irinotecan IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Procedure: computed tomography<br>* Correlative studies<br>* Other names: tomography, computed;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression, evaluated using RECIST | Kaplan-Meier estimates will be used. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate, evaluated using RECIST | 95% exact binomial confidence intervals will be used to describe the distribution. | Up to 1 year | 
| Complete response rate, evaluated using RECIST | 95% exact binomial confidence intervals will be used to describe the distribution. | Up to 1 year | 
| Duration of response, evaluated using RECIST |  | From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 1 year | 
| Survival | Kaplan-Meier estimates will be used. | Up to 1 year | 
| Incidence of toxicity, evaluated using CTCAE version 3.0 |  | Up to 1 year |