A Trial of ZD6474, Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiation Therapy Followed by Surgery
Condition: Cancer of the Esophagus; Adenocarcinoma of the Gastroesophageal Junction; Cancer of the Stomach
MeSH terms: Esophageal Neoplasms; Stomach Neoplasms
Intervention: Vandetanib; 5 Fluorouracil (FU); Carboplatin; Paclitaxel; External Beam Radiation Therapy (RT)
Intervention description: Vandetanib 100mg orally escalating to doses of 200 mg daily 7 days a week until completion of radiation therapy; 5-FU 225 mg/m2/day continuous infusion over96 hours during radiation therapy; Carboplatin AUC=5 days 1 and 29 during radiation therapy; Paclitaxel 50 mg/m2 days 1, 8, 15, 22, 29 during radiation therapy; External Beam Radiation Therapy(XRT)to a total dose of 4,500 centiGray (cGy) (180 cGy fractions daily) Monday through Friday for five weeks
Intervention MeSH terms: Paclitaxel; Carboplatin; Fluorouracil
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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
    

Eligibility criteria:

        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