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

Background:

- Most treatments for malignant pheochromocytomas/paragangliomas (PHEO/PGL) are palliative
and multidisciplinary. Chemotherapy using the combination of cyclophosphamide,
vincristine, and dacarbazine has been successfully utilized in the management of rapidly
progressive metastatic PHEO, with more than 50% complete or partial tumor response and
more than 70% complete or partial biochemical response.

- VEGF expression and evidence of angiogenesis has been found in many PHEO/PGL, so it is
plausible that interfering with VEGF signaling may result in anti-tumor activity in
patients with PHEO/PGL.

- Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial
growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the
anti-tumor activity of axitinib may result from its anti-angiogenic activity and that
this is reversible when treatment is discontinued.

- Given the known clinical safety and efficacy of axitinib, an assessment of its activity
in PHEO/PGL and its impact on the VEGF pathway in PHEO/PGL could provide valuable
information.

Objectives:

- Determine the response rate of metastatic PHEO/PGL to axitinib (AG-013736).

- Determine the progression-free survival of metastatic PHEO/PGL treated with axitinib
(AG-013736).

- Explore the relationship of potential biological markers of axitinib activity with
clinical outcomes.

- Perform pharmacogenomics analyses of drug metabolism and transport proteins through
germline DNA examination.

Eligibility:

- Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of Pathology,
NCI

- Biochemical evidence of PHEO/PGL

- Imaging confirmation of metastatic, locally advanced or unresectable disease.

- Measurable disease at presentation

- ECOG performance status less than or equal to 2

- Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor

Design:

- Phase II, open label, non-randomized trial

- Patients with metastatic pheochromocytoma/paraganglioma will receive axitinib (AG-013736
BID) in eight-week cycles

- Patients will be evaluated for response every twelve weeks (+/- 1 week) using RECIST
criteria

- Approximately 12 to 37 patients will be needed to achieve the objectives of the trial

- INCLUSION CRITERIA

2.1.1 Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by the
Laboratory of Pathology, 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 (F-DOPA, Dotatate, F-Dopamine or MIBG)

2.1.1.1 Imaging confirmation of metastatic disease

2.1.1.2 Measurable disease at the time of enrollment per RECIST 1.1.

2.1.1.3 A life expectancy of at least 3 months and 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 <18 years of a e, children are
excluded from this study, but will be eligible for future pediatric trials.

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

2.1.1.6 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

2.1.1.7 Last radiotherapy treatment greater than or equal to 4 weeks prior to starting
treatment with this protocol and there must be sites of measurable disease that did not
receive radiation

2.1.1.8 Prior therapeutic MIBG is allowed

2.1.1.9 Organ and marrow function as defined below:

2.1.1.10 Total bilirubin less than or equal to 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.

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.

2.1.1.11 AST less than or equal to 2.5 x ULN, ALT less than or equal to 2.5 x ULN

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

2.1.1.13 Creatinine clearance greater than or equal to 40 ml/min (estimated or measured
creatinine clearance) or serum creatinine less than or equal to 1.6 mg/dl

2.1.1.14 Random urine protein < 20 mg/dL. If greater than or equal to 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

2.1.1.15 Absolute neutrophil count greater than or equal to 500/mm(3)

2.1.1.16 Platelet count greater than or equal to 50,000/ mm(3)

2.1.1.17 Ability to understand and sign an informed consent document.

2.1.1.18 Ability and willingness to follow the guidelines of the clinical protocol
including visits to NICHD and NCI, Bethesda, Maryland for treatment and follow up visits.

2.1.1.19 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.

EXCLUSIONCRITERIA

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

2.1.2.2 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.

2.1.2.3 Unstable hypertension defined as a systolic blood pressure >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 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
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
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
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