First International Randomized Study in Malignant Progressive Pheochromocytoma and Paraganglioma

Exclusion Criteria

• •Large or small cell-poorly differentiated neuroendocrine carcinoma according to WHO 2000 classification
• •History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least three years.
• •Severe renal (GFR \<30ml/mn or nephrotic syndrome) or hepatic insufficiency (ALT / AST \> 2.5 x ULN or ALT/AST \>5 x ULN if liver function abnormalities are due to the underlying malignancy and/or total serum bilirubin \> 2.5 x ULN)
• •Patients with cardiac events within the previous 12 months, such as myocardial infarction (including severe/unstable angina pectoris), coronary/peripheral artery bypass graft, revascularization procedure symptomatic congestive heart failure (CHF, ejection fraction \<45%), ), uncontrolled cardiac arrhythmia, clinically significant bradycardia, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
• •Hypertension that cannot be controlled despite medications (\>=160/95 mmHg despite optimal medical therapy)
• •Abnormal cardiac function with 12 lead ECG. Ongoing cardiac dysrhythmias of NCI CTC grade \>=2, atrial fibrillation of any grade, or prolongation of the QTc interval to \>470 msec for males or \>480 msec for females.
• •Brain metastases (exception if stable and asymptomatic for more than 3 months)
• •Pregnancy or breast feeding
• •Previous treatment with the drug under study. Prior systemic treatment with any tyrosine kinase inhibitors or anti VEGF angiogenic inhibitors.
• •Current treatment with another investigational drug.
• •Treatment with potent CYP3A4 inhibitors and inducers within 7 and 12 days, respectively prior to study drug administration
• •Concomitant treatment with therapeutic doses of anticoagulants. Low dose warfarin (Coumadin) up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed as well as heparin-based anticoagulation
• •Prior treatments with chemotherapy, immunotherapy, somatostatine analog therapy drug , thoracic radiotherapy within 4 weeks prior to inclusion
• •Major surgery for any cause or local radiotherapy within one month prior to visit 1
• •Liver embolisation therapy within the last 3 months prior visit 1 except if progression is demonstrated and embolised lesion not used as targets
• •Unrecovered toxicity from any kind of therapy
• •Active or suspected acute or chronic uncontrolled disease that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.