Safety and Efficacy Study of PTK787/ZK222584 to Treat Metastatic Neuroendocrine Tumors (PTK787)

Inclusion Criteria:

• Biopsy-proven metastatic neuroendocrine tumors (which extent is disease is determined by CT scan or MRI) and biochemical evidence of disease.
• Evidence of progressive disease or inadequate controlled disease related syndrome symptoms.
• Must be receiving Sandostatin LAR 30mg every 4 weeks
• Age >or= to 18 years old
• Karnofsky Performance Status > or = 60
• Measurable lesion(s) as per the modified RECIST criteria
• Laboratory values <or= 2 weeks prior to randomization: ANC >or= 1.5 x 10(9)/L, Platelets >or= 100 x 10 (9), Hemoglobin >or= 9g/dL, Serum creatinine <or= 1.5 ULN, Serum bilirubin <or= 1.5 ULN, Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) <or= 3.0 x ULN (<or= 5 x ULN if liver metastases present), Negative for proteinuria based on dip stick reading OR documentation of 1+ result for protein on dip stick reading, then total urinary protein <or= 500mg and measured creatinine clearance >or= 50ml/min from a 24 hour urine collection.
• Life expectancy >or= 12 weeks.
• Written informed consent obtained according to local guidelines.

Exclusion Criteria:

• Had previous radiolabeled somatostatin analog therapy within the last 6 months.
• Hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease)
• Undergone cryoablation of hepatic metastasis within the last 2 months.
• History or presence of central nervous system (CNS) disease (ie:primary brain tumor, malignant seizures, CNS metastases or carcinomatous meningitis)
• History of another primary malignancy <or= 5 years, with the exception of inactive basal or squamous cell carcinoma of the skin.
• Prior chemotherapy <or= 3 weeks prior to registration and/or randomization. Patients must have recovered from all therapy-related toxicities.
• Prior biologic or immunotherapy <or= 2 weeks prior to registration and/or randomization. Patients must have recovered from all therapy-related toxicities.
• Prior full field radiotherapy <or= 4 weeks or limited field radiotherapy <or= 2 weeks prior to randomization. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.
• Major surgery (ie:laparotomy) <or= 4 weeks prior to randomization. Minor surgery <or= 2 weeks prior to randomization. Insertion of a vascular access device is not considered major or minor surgery in this regard. Patients must have recovered from all surgery-related toxicities.
• Patients who have received investigational drugs <or= 4 weeks prior to registration.
• Prior therapy with anti-VEGF agents
• Pleural effusion or ascites that causes respiratory compromise (>or= CTC grade 2 dyspnea)
• Female patients who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the trial in both sexes. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, therefore not considered effective for this study. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of study treatment.
• Uncontrolled high blood pressure, history of labile hypertension, or history of poor compliance with an antihypertensive regimen.
• Unstable angina pectoris
• Symptomatic congestive heart failure
• Myocardial infarction <or= 6 months prior to registration
• Active or uncontrolled infection
• Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
• Chronic renal disease
• Subjects at risk of significant cardiac arrythmias
• Uncontrolled diabetes
• Acute or chronic liver disease (eg:hepatitis, cirrhosis)
• Impairment of gastrointestinal function or GI disease that may significantly alter absorption (ie:ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow the tablets.)
• Confirmed diagnosis of human immunodeficiency syndrome (HIV) infection are excluded at the investigator's discretion.
• Patients taking therapeutic warfarin sodium (Coumadin) or similar oral anticoagulants that are metabolized by the cytochrome P450 system. Heparin is allowed.
• Patients unwilling or unable to comply with the protocol.
• Known symptomatic gallstones
• Received glucocorticoid therapy within the past 6 months, or who are currently receiving any chemotherapeutic agents, insulin sensitizers (eg:metformin, pioglitazone, rosiglitazone), or exogenous growth hormones.
• Subjects with unacceptable concomitant diagnoses, or who have received medication and/or therapies (ie:illness or therapies that would place patient at increased risk, or would, in the opinion of the investigator, interfere with the evaluation of efficacy or safety.)
• Exhibit symptoms indicative of intolerance of Sandostatin LAR.