First International Randomized Study in Malignant Progressive Pheochromocytoma and Paraganglioma

Inclusion Criteria:

* Diagnosis of malignant PPGL, based on imaging or biopsy evidence of metastases in liver, bones, lungs and or lymph nodes, combined with at least one of two further confirmatory diagnoses: 1. diagnosis of PPGL from histopathological review of resected or biopsied tissue performed by a skilled pathologist (centralized review will be performed in all cases either before enrolment in case of any doubt or during the study); or 2. in patients where tumor tissue is unavailable for formal pathological review, from combined biochemical and functional imaging evidence of PPGL (e.g., MIBG scintigraphy combined with consistently and highly elevated plasma or urine levels of metanephrines).
* Metastatic disease not amenable to surgical resection
* Pre-treated or not
* Whatever the genetic status (sporadic or inherited)
* Evaluable disease according to RECIST 1.1 criteria
* Progressing disease within 18 months at imaging prior to randomization according to RECIST. The recent scan indicating progression may be used as the screening scan if within 28 days of randomization
* ECOG performance status 0-2
* Life expectancy ≥ 6 months as prognosticated by the physician
* Age ≥18 years, no superior limit
* Adequate bone marrow reserve (Hb \> 8, neutrophils ≥ 1500/mm³ and platelets ≥80.000/mm³)
* Effective contraception in pre-menopausal female and male patients
* Negative pregnancy test
* Patient´s signed written informed consent
* Ability to comply with the protocol procedures
* Ability to take oral medication

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.