A Trial of ZD6474, Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiation Therapy Followed by Surgery

Study Overview
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Brief Summary
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The purpose of the study is to determine the most tolerable and safe dose of ZD6474 (Zactima, Vandetanib) when given with standard chemotherapy, radiation therapy and surgery in patients with cancer of the esophagus

Detailed Description
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Epidermal Growth Factor Receptor (EGFR) is known to be an important prognostic factor for patients with esophageal cancer-overexpression is associated with a worse prognosis. Review of the literature demonstrates presence of EGFR expression in up 90% of cases of esophageal cancer. Additionally, Vascular Endothelial Growth factor (VEGF) is commonly overexpressed in esophageal cancer (especially adenocarcinoma) and is linked to the transition from Barrett's esophagus to invasive adenocarcinoma. Esophageal cancers with overexpression of VEGF are associated with a worse prognosis and poorer response to conventional chemoradiation. Therefore, we feel it would be valuable to add an inhibitor of EGFR and VEGFR to the therapy of esophageal cancer to increase the rate of pathologic complete response and thus improve overall survival. In current trials of ZD6474 in combination with chemotherapy, the dose has been 300mg. We will perform a phase I trial in which we will dose-escalate ZD6474 to determine if this drug is tolerable in combination with cytotoxic chemotherapy and external beam radiation therapy. This would be the first trial in humans in which f these three modalities would be combined. We will determine the maximum tolerated dose of ZD6474 in this small trial and then hope to perform a larger phase II trial, perhaps in the context of the Radiation Therapy Oncology Group (RTOG).

Official Title
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Induction Therapy for Locally Advanced, Resectable Cancer of the Esophagus, Gastroesophageal (GE) Junction and Gastric Cancer: A Phase I Trial of ZD6474 (Zactima, Vandetanib), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiation Therapy Followed by Surgery

Conditions
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Cancer of the Esophagus, Adenocarcinoma of the Gastroesophageal Junction, Cancer of the Stomach

Intervention / Treatment
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* Drug: Vandetanib
* Drug: 5 Fluorouracil (FU)
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: External Beam Radiation Therapy (RT)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically documented carcinoma of the esophagus, gastroesophageal junction, or stomach for which chemo/radiation therapy is appropriate. Potentially resectable esophageal, Gastroesophageal junction carcinoma, or stomach carcinoma Eastern Cooperative Oncology Group Performance Status = 0-2 No evidence of distant metastases Age 18 or greater Signed informed consent Willingness to practice adequate contraception in women of childbearing potential (WOCBP). Contraception must be continued for one month following discontinuation of the study drugs. Females who are WOCBP must have negative pregnancy test within 7 days of the first treatment. WOCBP includes any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is postmenopausal (defined as amenorrhea >=12 consecutive months, or women on hormone replacement therapy (HRT) with documented plasma follicle-stimulating hormone (FSH) level >35 mIU/mL). Even women who are using oral, implanted, or injectable contraceptive hormones or mechanical products (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g. vasectomy), should be considered to be WOCBP. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Exclusion criteria: Previous radiation therapy to chest or upper abdomen. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. Impaired cardiac function at baseline, including any of the following: Clinically significant cardiac event such as myocardial infarction; New York Heart Association (NYHA) classification of heart disease >2 within 3 months before registration; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia. Inadequate pulmonary and cardiac function to tolerate surgery (see section 12): left ventricular ejection fraction <45% and/or a positive stress test; or Forced Expiratory Volume (FEV1) of <1.1 liters. History of arrhythmia (multifocal premature ventricular contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded. Previous history of QTc prolongation as a result from other medication that required discontinuation of that medication. Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age. Presence of left bundle branch block (LBBB). QTc with Bazett's correction that is unmeasurable, or >or= 480 msec on screening ECG. If a patient has QTc >or= 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be <480 msec in order for the patient to be eligible for the study). Any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes or induce CYP3A4 function Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg) Women who are currently pregnant or breast feeding. Previous or current malignancies within the last 5 years, with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin Receipt of any investigational agents within 30 days prior to commencing study treatment. Uncontrollable diarrhea that may affect the ability of the patient to absorb ZD 6474 or tolerate side-effects. Laboratory results: Adequate bone marrow function as defined by granulocyte count < 1500/mm^3 and platelet count < 100,000 Serum bilirubin >1.5x the upper limit of reference range (ULRR) Serum creatinine >1.5 x ULRR or creatinine clearance < 50 mL/minute (calculated by Cockcroft-Gault formula.) Potassium < 4.0 mmol/L despite supplementation; serum calcium (ionized or adjusted for albumin,) or magnesium out of normal range despite supplementation. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 X ULRR

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 |
| --- | --- |
| Other: Vandetanib<br>Vandetanib 100 mg (6 patients) or 200 mg (3 patients) orally daily during the conventional 3D-guided conformal radiation therapy plus chemotherapy with carboplatin (AUC 5) on days 1 and 29, paclitaxel 50 mg/m2 i.v. weekly on days 1, 8, 15, 22, 29; and continuous infusion of 5-fluorouracil at 225 mg/m2 for 96 hours Monday-Friday during the radiation. | Drug: Vandetanib<br>* Vandetanib 100mg orally escalating to doses of 200 mg daily 7 days a week until completion of radiation therapy<br>* Other names: Zactima;Drug: 5 Fluorouracil (FU)<br>* 5-FU 225 mg/m2/day continuous infusion over96 hours during radiation therapy<br>* Other names: 5-FU;Drug: Carboplatin<br>* Carboplatin AUC=5 days 1 and 29 during radiation therapy<br>Drug: Paclitaxel<br>* Paclitaxel 50 mg/m2 days 1, 8, 15, 22, 29 during radiation therapy<br>* Other names: Taxol;Radiation: External Beam Radiation Therapy (RT)<br>* External Beam Radiation Therapy(XRT)to a total dose of 4,500 centiGray (cGy) (180 cGy fractions daily) Monday through Friday for five weeks<br>* Other names: RT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Vandetanib | To determine the maximum tolerated dose (MTD) of Vandetanib given concurrently with chemotherapy and radiation therapy followed by surgery (esophagectomy)evaluated by the frequency, severity and duration of adverse events that occur during treatment and for four weeks following surgery as measured by serial blood tests, electrocardiograms and physical assessments | Within 4 weeks of initiation of chemo/radiation therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Adverse Events | To determine the safety and tolerability of Vandetanib when given in combination with chemotherapy and radiation therapy as evaluated by serial blood tests, electrocardiograms, and physical assessments during therapy and for four weeks following surgery | Within 4 weeks of initiation of chemo/radiation therapy |