NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma
NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma
The purpose of this study is to see how well the study drug, axitinib, helps control renal
 (kidney) cancer that has come back (recurrent) or spread (metastatic). Patients must have
 already been treated as a participant in a clinical trial with sunitinib, sorafenib,
 pazopanib or placebo (sugar pill) after their initial surgery.

 This study will examine the effect of adjuvant tyrosine kinase inhibition (TKI) therapy
 (sorafenib, sunitinib or pazopanib) on subsequent exposure to TKI with axitinib in the
 first-line recurrent or metastatic setting.
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