Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma

• INCLUSION CRITERIA

2.1.1 Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by the Laboratory of Pathology, National Cancer Institute (NCI) when such tissue is available to confirm or

In the event that outside tissue is not available:

• an outside pathology report confirms the diagnosis of Pheo-PGI, AND
• the patient has nuclear medicine imaging studies that would only be positive in an adult patient with a diagnosis of Pheo/PGL (Fluorodopa (F-DOPA), Dotatate, F-Dopamine or Metaiodobenzylguanidine (MIBG))

2.1.1.1 Imaging confirmation of metastatic disease

2.1.1.2 Measurable disease at the time of enrollment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

2.1.1.3 A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

2.1.1.4 Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Axitinib in patients 150 mm Hg or diastolic pressure > 90 mmHg despite optimal medical management.

2.1.2.4 Untreated brain metastases (or local treatment of brain metastases within the last 6 months) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic adverse events.

2.1.2.5 Pregnancy, due to the possible adverse effects on the developing fetus.

2.1.2.6 Lactating women who are breast-feeding due to the possibility of transmitting axitinib to the child.

2.1.2.7 The presence of a second malignancy, other than squamous cell carcinoma of the skin or in situ cervical cancer because it will complicate the primary objective of the study. Cancer survivors who have been free of disease for at least two years can be enrolled in this study.

2.1.2.8 Patients with evidence of a bleeding diathesis

2.1.2.9 Patients must not have received prior therapy with a tyrosine kinase inhibitor (TKI). Prior TKI usage in pheochromocytoma affects the same pathway as axitinib.

2.1.2.10 Gastrointestinal abnormalities including:

• Inability to take oral medications
• Requirement for intravenous alimentation
• Prior surgical procedure affecting absorption including total gastric resection
• Treatment for active peptic ulcer disease in the past 6 months
• Active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy
• Malabsorption syndrome

2.1.2.11 Current use or anticipated need for treatment with drugs that are known potent Cytochrome P450 3A4 (CYP3A4) inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and delavirdine).

2.1.2.12 Current use or anticipated need for treatment with drugs that are known CYP3A4 or Cytochrome P450 1A2, (CYP1A2) inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. John's wort).

2.1.2.13 Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access devices or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.

2.1.2.14 Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.

2.1.2.15 Any of the following within 12 months prior to study drug administration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and within 6 months before study drug administration for deep vein thrombosis or pulmonary embolism.

2.1.2.16 Other severe acute or chronic medical or psychiatric condition, or laboratory