A Pilot Study of SBRT With Adjuvant Pazopanib for Renal Cell Cancer

PRIMARY OBJECTIVES:

I. To determine the rate of treatment related toxicity reports following stereotactic body
radiation therapy (SBRT) and pazopanib (pazopanib hydrochloride) as a determination of the
tolerability of combined therapy in patients with clear cell renal cell carcinoma (RCC).

SECONDARY OBJECTIVES:

I. To determine the tumor diameter/volume change prior to and following pazopanib treatment
prior to SBRT.

II. To determine the impact of pre SBRT pazopanib therapy on radiation therapy target
volumes for evidence of tumor shrinkage.

III. To evaluate tumor change in radiation therapy target volumes and the incidence of
treatment related toxicity reports and sparing of non-involved nephron.

IV. Report change in tumor control following pazopanib and SBRT as evaluated by post
treatment repeat biopsy and/or Response Evaluation Criteria in Solid Tumors (RECIST)
criteria.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) daily for up to 60 days. Patients then
continue to receive pazopanib hydrochloride PO daily and undergo SBRT every other day over
days 60-65.

After completion of study treatment, patients are followed up at 1, 3, 6, 12, 18, and 24
months.

Inclusion Criteria:

- Patient is considered a poor surgical candidate for removal of a renal mass as
determined by pre-operative assessment due to the following factors or various
combinations thereof:

- Significant comorbidity precluding ability to deliver anesthesia, without
compromised ability to undergo systemic chemotherapy with pazopanib as deemed by
the Urologist and Medical Oncologist

- Medically documented contraindication for surgery due to religion or risk of
blood transfusion

- Size or location of tumor deemed high risk for surgical intervention by
Urologist

- Unacceptable risk for anesthesia, such as history of malignant hyperthermia

- Any one of these factors may or may not constitute unresectability, but for
consideration for this trial, the surgical and medical oncologist must agree
that the particular constellation of findings for the patient under
consideration would likely entail a low probability (< 50%) that the tumor would
be resectable (with negative margins) or that the potential morbidity associated
with an attempt at surgical resection would not be clinically acceptable

- The numerical thresholds noted above are only a guideline and the clinical
judgment of the surgeon and medical oncologist will determine unresectability or
if patient refuses surgery or other forms of local therapy; the histopathology
for this cohort is limited to clear cell carcinoma of the kidney

- Patient is able to give and sign study specific informed consent

- Negative serum or urine pregnancy test within 72 hours prior to registration for
women of childbearing potential and agrees to use contraception for the duration of
the treatment cycle and for a minimum of 30-days following the end of therapy (a
minimum estimate 95 days)

- Patient has a pathologically confirmed diagnosis of clear cell RCC

- Karnofsky status of ≥ 70%

- Subject has no contraindication for computed tomography (CT) and/or magnetic
resonance imaging (MRI) during screening and is able to complete a screening
examination; CT and/or MRI within 6 months of screening is required

- Patient has inadequate organ function as defined by:

- Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase
[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase
[SGPT]) =< 2.5 x laboratory upper limit of normal (ULN)

- Total serum bilirubin < 1.5 x ULN

- Absolute neutrophil count (ANC) > 1500/uL

- Platelets > 100,000/uL

- Hemoglobin > 9.0 g/dL (no transfusion permitted within 1 week)

- Serum creatinine < 2.5 mg/dL

- Urine to protein to creatinine (UPC) ratio < 1; if UPC > 1, then a 24-hour urine
protein must be assessed; subjects must have a 24-hour urine protein value < 1 g
to be eligible

- Prothrombin time (PT) or international normalized ratio (INR) and partial
thromboplastin time (PTT) < 1.2 X upper limit of normal (ULN)

Exclusion Criteria:

- Any patient with active connective tissue disease such as lupus, dermatomyositis

- Major psychiatric illness, which would prevent completion of treatment or interfere
with follow-up

- Prior dose of radiation overlapping the treatment field determined by a study
Radiation Oncologist to represent unacceptable risk for additional radiation to be
targeted to the field

- Pregnant and lactating females, and unwillingness to use contraception; or male
subject not willing to use contraception during and for 21 days after the last dose
of pazopanib therapy

- Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding (e.g. active peptic ulcer, ulcerative colitis, Crohn's
disease, abdominal fistula) within prior 6 months

- Clinically significant gastrointestinal abnormalities that may affect absorption
(e.g. malabsorption syndrome, major resection of the stomach or small bowel)

- Corrected QT interval (QTc) > 480 msecs (record QTc correction method)

- History of clinically significant cardiovascular condition with the past 6 months
(e.g. angioplasty or stenting, myocardial infarction, unstable angina, bypass
surgery, symptomatic peripheral arterial disease [PAD], class III or IV congestive
heart failure)

- History of cerebrovascular accident within the past 6 months (e.g. transient ischemic
attack [TIA])

- Poorly controlled hypertension (systolic blood pressure [SBP] >= 140 mmHg or
diastolic blood pressure [DBP] >= 90 mmHg); the initiation or adjustment of
antihypertensive medication(s) is permitted prior to study entry

- Major surgery or trauma within 29 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture or ulcer (catheter placement is not major
surgery)

- Evidence of active bleeding or bleeding diathesis

- Recent hemoptysis (>= half teaspoon of red blood within 8 weeks before first dose of
study drug)

- Treatment with any other anti-cancer therapies (e.g. other radiation, surgery or
tumor embolization) within the last 14 days prior to first dose of study drug; or
chemotherapy, immunotherapy, biologic therapy, investigational or hormonal therapy
within 14-days (or 5 half-lives of a drug whichever is longer) prior to the first
dose of the study drug pazopanib