NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma

Approximately 64,770 cases of cancer involving the kidney and renal pelvis were diagnosed in
the United States in 2012 and 13,570 deaths occurred from these tumors. The rate of Renal
Cell Carcinoma (RCC) has increased by 2% per year for the past 65 years. The reason for this
increase in unknown but smoking and obesity are risk factors for the development of RCC.
Early stage disease is typically treated with resection with definitive intent with partial
or radical nephrectomy. Patients with metastatic disease are often treated with systemic
therapy with palliative intent. Systemic therapeutic options include so-called targeted
therapies, and less often chemotherapy and immunomodulatory therapies (interferon alpha and
interleukin-2).

The Food and Drug Administration (FDA) has approved six targeted agents for the treatment of
advanced and metastatic renal cell carcinoma that fall into two general classes - vascular
endothelial growth factor (VEGF) inhibitors and inhibitors of mammalian target of rapamycin
(mTOR). On the basis of several randomized phase III studies, vascular endothelial growth
factor receptor-2 (VEGFR2) inhibitor therapy has become the generally preferred treatment
for recurrent and metastatic ccRCC (clear cell Renal Cell Carcinoma) in the first-line
setting. Treatment of ccRCC with VEGF-inhibition in the first-line metastatic setting, is
associated with a progression-free survival of approximately 11 months. Vascular endothelial
growth factor (VEGF) inhibitor therapy in the second-line remains active, but to a lesser
degree - progression-free survival (PFS) has been reported to be between 5 and 7 months.

Adjuvant treatment of high-risk, early-stage ccRCC with VEGFR2 TKI therapy following
definitive resection has become an area of active investigation. The ASSURE trial (ECOG
2805) recently completed accrual, and other adjuvant trials - i.) SORCE (sorafenib for 3 or
1 year versus placebo), ii.) S-Trac (sunitinib versus placebo) - are in accrual.

Axitinib (AG-013736, Pfizer Inc.), a receptor-tyrosine kinase inhibitor that is selective
for VEGFR1, 2, and 3, is an important new agent for use in metastatic RCC. Axitinib has been
examined extensively in RCC, and it has been shown to be safe, well-tolerated, and highly
active. On January 27, 2012, the FDA approved axitinib for the treatment of advanced RCC
after failure of one prior systemic therapy.

Inclusion Criteria:

- Locally recurrent or metastatic RCC requiring systemic therapy following treatment
(tx) with sorafenib, sunitinib, pazopanib, or placebo on an adjuvant study

- Required to have primary or recurrence tumor samples containing clear cell variant
RCC with <50% of any other histology

- Recurrence must occur ≥ 3 months following end of exposure to the adjuvant
intervention

- Received ≥ 3 six week cycles of prior adjuvant tx with sorafenib, sunitinib,
pazopanib or placebo in the adjuvant setting on a clinical trial, or recurrence >3
months of tx on an adjuvant placebo arm

- Required to have measurable recurrent or metastatic disease that is not curable by
standard radiation therapy or surgery

- Male or female, ≥ 18 years old

- ECOG PS 0 or 1

- Blood pressure (B/P) must be controlled at time of enrollment. Tx with
antihypertensive medication(s) is allowed. Controlled B/P is defined as in clinic
measurement of systolic B/P ≤ 140 mm Hg AND diastolic B/P ≤ 90 mm Hg. If B/P is
uncontrolled at time of planned enrollment, tx or optimization with antihypertensive
medication(s) may be initiated in order to control B/P. Patient may be considered for
enrollment when this has happened.

- Women must not be pregnant or breastfeeding

- Men and women who are of reproductive potential must be willing to employ an
effective method of birth control/contraception

- Willingness and ability to comply with scheduled visits, tx plans, laboratory tests,
and other study procedures

- Ability to understand and willingness to sign an IRB-approved informed consent

- Adequate organ function as evidenced by the following, obtained within 28 days prior
to registration:

- Absolute neutrophil count (ANC) ≥ 1250 cells/mm³

- Platelet count ≥ 75,000 cells/mm³

- Hemoglobin ≥ 9.0 g/dL

- Total direct serum bilirubin ≤ 1.5x upper limit of normal (ULN)

- ALT and AST ≤ 2.5 x ULN unless there are liver metastases in which case AST and
ALT ≤ 5.0 x ULN

- Serum creatinine <1.5 x ULN or calculated creatinine clearance ≥ 45 mL/min

- Urine protein <2+ by urine dipstick

- Resolution of all previous tx-related toxicity to ≤ grade 1 or back to baseline

- No major surgery <4 weeks or radiation therapy <2 weeks of starting study tx. Prior
palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at
least one measurable lesion that has not been irradiated.

- No clinically significant gastrointestinal abnormalities

- No current use or anticipated need for tx with drugs that are known potent CYP3A4
inhibitors

- No current or anticipated need for tx with drugs that are known CYP3A4 or CYP1A2
inducers

- No current requirement of anticoagulant therapy with oral vitamin K antagonists

- No untreated brain metastases, spinal cord compression, or carcinomatous meningitis.
Patients must be off oral (systemic) steroids prior to registration. Inhalational
steroids, e.g., for asthma, emphysema are permissible.

- No serious uncontrolled medical disorder or active infection that would impair their
ability to receive study tx

- None of the following conditions within the 6 months prior to study drug: myocardial
infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebrovascular accident, transient ischemic attack, deep
vein thrombosis or pulmonary embolism

- No known HIV or AIDS-related illness

- No other active malignancy

- No dementia or significantly altered mental status that would prohibit the
understanding or rendering of informed consent and compliance with the requirements
of the protocol

- No other severe acute/chronic medical or psychiatric condition or lab 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