Phase II Study of ZD6474 in Advanced NSCLC
Condition: Lung Cancer
MeSH terms: Lung Neoplasms
Intervention: ZD6474; Carboplatin; Paclitaxel
Intervention description: ZD6474 alone: Cycles 1-3 = 300 mg PO Daily x 3 Weeks; ZD6474+Carboplatin+Paclitaxel = 300 mg oral (PO) Daily or 100 mg PO Daily plus Carboplatin and Paclitaxel Every 3 Weeks.; 6 AUC IV Over 15-30 Minutes, Immediately After Paclitaxel; 200 mg/m^2 IV Over 3 Hours On Day 1
Intervention MeSH terms: Paclitaxel; Carboplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Non-Small Cell Lung Cancer; Lung Cancer; Carboplatin; Paclitaxel; ZD6474; NSCLC

Summary:

      The goal of this clinical research study is to learn how the drug ZD6474 affects the amount
      of tumor cell death in the body and the amount of blood that can be supplied to the tumor.
      The safety of ZD6474 alone and when given with chemotherapy will be studied. In addition, the
      side effects and response to this treatment will also be studied.
    

Eligibility criteria:

        Inclusion Criteria:

          1. An informed consent form must be completed before any protocol specific screening.
             Patient must consent to a tissue biopsy at study entry and again at the week 3.

          2. Patients must have a diagnosis of stage IIIb or stage IV non-small cell lung cancer
             (histologically or cytologically proven) and must not be eligible for combined
             chemotherapy and radiation therapy.

          3. Patients must have at least one site of measureable disease that is amenable to
             biopsy. The patient must not have had radiation to this site. Lesion must be at least
             20 mm in the longest diameter by spiral CT or 20 mm with conventional techniques
             according to RECIST.

          4. Eligible patients must have an ECOG performance status of 0-1.

          5. Patients must have adequate hepatic, renal, and bone marrow function as defined below:
             1) Serum creatinine < 1.5 mg/dL or a calculated creatinine clearance > 60 mL/min 2)·
             Total bilirubin < 1.5 x ULN ·3) ALT or AST </= 2.5 x ULN OR ALT or AST </= 5.0 x ULN
             if related to liver metastases OR Alk Phos </= 2.5 x ULN ·4) WBC > 3,000/mm**3 ·5) ANC
             > 1,500 mm**3 ·6) Platelets > 100,000/mm**3 ·7) Hemoglobin > 10 g/dL ·8) PT/PTT < 1.5
             x normal

          6. Patients must be >= 18 years of age.

        Exclusion Criteria:

          1. Patients are excluded if they have received prior chemotherapy for this disease type.

          2. Patients with brain metastases are not eligible for this study unless treated at least
             4 weeks before entry and stable without steroid treatment for 1 week.

          3. Prior radiation therapy allowed to <25% of the bone marrow. Prior radiation to the
             whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks
             before study enrollment. Patients must have recovered from the acute toxic effects of
             the treatment prior to study enrollment.

          4. Patients may not have any concomitant uncontrolled medical or psychiatric disorders.

          5. Patients must not be pregnant or breast-feeding. All women of childbearing potential
             must have a negative pregnancy test. Childbearing potential will be defined as women
             who have had menses within the past 12 months, who have not had tubal ligation or
             bilateral oophorectomy. There is no specific information available on the effects of
             this drug on women who are pregnant or breast-feeding. Therefore these patients are
             excluded from this study because of the unknown risks involved. All sexually active
             patients must practice adequate contraception for the entire treatment period.

          6. Patients must not have undergone minor surgery (e.g., central venous catheter
             placement) within 24 hours of treatment with ZD6474. Patients may not have undergone
             any major surgery (e.g., laparotomy, thoracotomy, or craniotomy) within four weeks of
             enrollment.

          7. Patients may not have a history of a bleeding diathesis.

          8. Patients must agree not to use herbal remedies or other over-the-counter biologics
             (e.g., shark cartilage)

          9. Significant cardiac event (including symptomatic heart failure or angina) within 3
             months of entry or presence of cardiac disease that in the opinion of the Investigator
             increase the risk of ventricular arrythmia.

         10. History of clinically significant arrhythmia (multifocal PVCs, bigeminy, trigeminy,
             ventricular tachycardia) which is symptomatic or requires treatment (CTC grade 3) or
             asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on
             medication is not excluded.

         11. Presence of left bundle branch block (LBBB).

         12. Previous history of QT prolongation as a result from other medication that required
             discontinuation of that medication.

         13. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under
             40 years of age.

         14. QTc with Bazett's correction that is unmeasurable, or >/= 480 msec on screening ECG.
             If a patient has QTc >/= 480 msec on screening ECG, the screening may be repeated
             twice (at least 24 hours apart). The average QTc from the 3 screening ECGs must be <
             480 msec in order for the patient to be eligible for the study.

         15. Any concomitant medications that may cause QTc prolongation or induce Torsades de
             Pointes (see Appendix F) or induce CYP3A4 function (see section 8.2).

         16. Potassium level less than 3.5 meq/l; calcium and magnesium level outside normal
             limits. Supplementation of electrolytes is permitted.

         17. Left ventricular ejection fraction less than 45% measured by echocardiogram for
             subjects with previous anthracycline therapy (total dose greater than 450 mg/m2),
             significant cardiovascular disease, or chest irradiation

         18. History of severe hypersensitivity reaction to drugs formulated with polysorbate 80

         19. Any concurrent condition which in the investigator's opinion makes it undesirable for
             the subject to participate in the trial or which would jeopardize compliance with the
             protocol.

         20. Participation in an investigational trial within the past 30 days.

         21. Because of DCE-MRI, individuals with the following are excluded: 1) Cardiac pacemakers
             or neurostimulators, 2) Metal implants other than those approved as being safe in an
             MRI environment, 3) Claustrophobia, 4) Physical characteristics that preclude a MRI
             scan

         22. Hypertension not controlled by medical therapy (systolic blood pressure greater than
             160 mm Hg or diastolic blood pressure greater than 100 mm Hg)

         23. Currently active diarrhea that may affect the ability of the patient to absorb the
             ZD6474 or tolerate diarrhea.

         24. Previous or current malignancies at other sites within the last 5 years, with the
             exception of cervical carcinoma in situ and adequately treated basal cell carcinoma or
             squamous cell carcinoma of the skin.