Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma

The long-term survival for malignant pheochromocytoma/paraganglioma (PHEO/PGL) may be limited
because of its hormonal effects as well as its aggressive behavior and dissemination,
particularly in some hereditary PHEO/PGL. Although several therapeutic modalities have been
used to palliate malignant PHEO/PGL, a continued search for new agents to address the
malignancy is needed to improve outcomes. One approach is to utilize drugs that target
signaling pathways leading to decreased proliferation and survival of cancer cells. Some data
in the literature suggests that in malignant PHEO/PGL, VEGF seems to play a role in the
biology of the cancer and thus, its inhibition could reduce tumor growth. Sunitinib and
imatinib has been used in a limited number of malignant pheochromocytomas with varying
responses. Axitinib was designed to inhibit VEGFR that participates in tumor angiogenesis. In
order to determine the activity of axitinib in tumor and hormonal responses in malignant
PHEO/PGL, it will be used as a single agent in this study. The combination of
cyclophosphamide; vincristine and dacarbazine have been shown to produce partial responses in
malignant PHEO/PGL. The majority of the patients may have already received this combination
or will receive this combination chemotherapy in the future. The goal is to develop multiple
lines of effective treatments for this disease.

Inclusion Criteria

Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by a
CUMC/NYPH laboratory when such tissue is available to confirm.

In the event that outside tissue is not available:

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

- Imaging confirmation of metastatic disease

- Measurable disease at the time of enrollment as per RECIST 1.1.

- A life expectancy of at least 3 months and ECOG performance status ≤ 2

- Age ≥ 18 years

- Information available or pending regarding possible genetic alterations that can
explain the patient's pheochromocytoma/paraganglioma (mutations in SDHB, SDHV or VHL
genes)

- Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the
case of nitrosourea) prior to enrollment date; 2 weeks if the last therapy was
received as part of a "phase 0" or "exploratory IND" trial. Last surgery more than 4
weeks prior to enrollment, to allow for wound healing. Core biopsies or FNA will not
require any waiting period

- Last radiotherapy treatment ≥ 4 weeks prior to starting treatment with this protocol
and there must be sites of measurable disease that did not receive radiation

- Prior therapeutic MIBG is allowed

- Organ and marrow function as defined below:

- Total bilirubin ≤ 1.5 x ULN (upper limit of normal), unless the patient meets the
criteria for Gilbert's Syndrome. The upper limit value for bilirubin for subjects with
Gilbert's Syndrome is less than 3 mg/dl.

o Note: A diagnosis of Gilbert's disease will be made in the presence of (1)
unconjugated hyperbilirubinemia noted on several occasions; (2) normal results from
CBC count, reticulocyte count, and blood smear; (3) normal liver function test
results; and (4) an absence of other disease processes that can explain the
unconjugated hyperbilirubinemia.

- AST ≤ 2.5 x ULN, ALT ≤ 2.5 x ULN

- Amylase and lipase equal to, or less than, the institutional ULN.

- Creatinine clearance ≥ 40 ml/min (estimated or measured creatinine clearance) or serum
creatinine ≤ 1.6 mg/dl

o Random urine protein < 20 mg/dL. If ≥ 20 mg/dL then a 24-hour urine protein
collection will be performed to accurately demonstrate that the 24-hour total is <1000
mg, the level acceptable for enrollment on study

- Absolute neutrophil count ≥ 500/mm3

- Platelet count ≥ 50,000/ mm3

- Ability to understand and sign an informed consent document.

- Ability and willingness to follow the guidelines of the clinical protocol.

- Because the effects of chemotherapy on the developing human fetus are potentially
harmful, women of childbearing potential and men who participate in the study must
agree to use adequate contraception (hormonal or barrier methods) before, during the
study and for a period of 3 months after the last dose of chemotherapy.

Exclusion Criteria

- Patients with pheochromocytoma/paraganglioma tumors potentially curable by surgical
excision alone as determined by the Principal Investigator in discussions with the
surgical consultants

- Patients who have large abdominal masses impinging on bowel or pulmonary masses with
encroached vessels and a potential to bleed will be considered on case by case basis
after careful consultation with multiple disciplines such as radiologists and surgeons
with main intent being patient safety.

- Unstable hypertension defined as a systolic blood pressure >150 mm Hg or diastolic
pressure > 90 mmHg despite optimal medical management.

- Untreated brain metastases (or local treatment of brain metastases within the last 3
months) due to the poor prognosis of these patients and difficulty ascertaining the
cause of neurologic adverse events.

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

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

- 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 one year can be enrolled
in this study.

- Patients with evidence of a bleeding diathesis

- Patients must not have received prior therapy with a TKI. Prior TKI usage in
pheochromocytoma affects the same pathway as axitinib.

- 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

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

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

- 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.

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

- 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.

- Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the patient inappropriate for entry into
this study.