Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer

Background:

- The response rates of recurrent, metastatic and unresectable adrenocortical cancer
(ACC) to mitotane, doxorubicin, etoposide, and cisplatin are low and underscore the
need for more effective systemic therapies.

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

- 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 ACC and its impact on the VEGF pathway in ACC could provide valuable information.

Objectives:

- Determine the response rate of axitinib (AG-013736) in recurrent, metastatic, or
primary unresectable ACC

- Determine the progression-free survival

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

- Explore the pharmacogenetic analyses of drug metabolism and transport proteins through
germline DNA examination.

Eligibility:

- Adults with pathologic confirmation of ACC by the Laboratory of Pathology, NCI

- Diagnosis of recurrent, metastatic, or primary unresectable ACC

- 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 recurrent, metastatic, or primary unresectable ACC will be given in eight
weeks cycles with BID dosing of axitinib (AG-013736).

- Patients will be evaluated for response every eight weeks using RECIST criteria.

- Tumor biopsies are not mandatory but every attempt will be made to obtain these from
patients prior to starting axitinib and again 20-30 days after treatment has begun.

- Approximately 40 patients will be needed to achieve the objectives of the trial.

- INCLUSION CRITERIA:

1. Pathologic confirmation of adrenocortical cancer by the Laboratory of Pathology,
NCI.

2. Measurable disease at presentation.

3. A life expectancy of at least 3 months and ECOG performance status less than or
equal to 2.

4. Age greater than or equal to 18 years.

5. 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.

6. 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.

7. Prior mitotane therapy is allowed. Patients with a history of a functional tumor
who are receiving mitotane to control the excess hormone production may continue
to receive mitotane.

8. Organ and marrow function as defined below:

- 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.

- AST less than or equal to 2.5 times ULN, ALT greater than or equal to 2.5 times ULN

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

- Creatinine clearance greater than or equal to 40 ml/min (measured in a timed urine
collection) or serum creatinine less than or equal to 1.6 mg/dl

- Absolute neutrophil count greater than or equal to 1000/mm(3).

- Platelet count greater than or equal to 100,000/ mm(3).

9. Ability to understand and sign an informed consent document.

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

11. Because the effects of chemotherapy on the developing human fetus are potentially
harmful, women of childbearing potential and men 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:

1. Patients with adrenocortical tumors potentially curable by surgical excision alone as
determined by the Principal Investigator in discussions with the surgical
consultants.

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.

3. Unstable hypertension defined as a systolic blood pressure greater than 140 mm Hg or
diastolic pressure greater than 90 mmHg despite optimal medical management and
patients who are receiving more than 1 antihypertensive agent at trial entry, (not
including spironolactone) unless the patient has Cushing's Disease with its
associated hypertension and is well controlled on medications.

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.

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

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

7. The presence of a second malignancy, other than a skin cancer 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.

8. Patients with evidence of a bleeding diathesis.

9. Phosphorus level equal to, or less than, the institutional lower limits of normal
that cannot be corrected.

10. Gastrointestinal abnormalities including:

1. inability to take oral medications

2. requirement for intravenous alimentation

3. prior surgical procedure affecting absorption including total gastric resection

4. treatment for active peptic ulcer disease in the past 6 months

5. 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

6. malabsorption syndrome

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, atazonavir, amprenavir, fosamprenavir, and
delavirdine).

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

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

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

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 6
months for deep vein thrombosis or pulmonary embolism.

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.

17. Current use of drugs that are known inhibitors or inducers of BCRP and OATP1B1/3 or
known to affect protein binding should be used with caution and with acknowledgement
of the PI.