Pazopanib Hydrochloride in Treating Patients With Stage IV Kidney Cancer

PRIMARY OBJECTIVES:

I. To determine the response rate (RR) associated with pazopanib (pazopanib hydrochloride) as
3rd-line therapy in metastatic renal cell carcinoma (mRCC) patients who have failed therapy
with a distinct vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI).

SECONDARY OBJECTIVES:

I. To determine if baseline hepatocyte growth factor (HGF), endothelial selectin (E-selectin)
and interleukin-6 (IL-6) are associated with progression-free survival (PFS).

II. To determine if pre-metastatic niche density in regional lymph nodes (LNs) is associated
with PFS.

III. To determine an association between E-selectin, IL-6 and pre-metastatic niche density.

IV. To evaluate the prognostic effect of pre-metastatic niches as an independent factor in
time to first relapse.

V. To determine if phosphorylated signal transducer and activator of transcription 3 (pSTAT3)
in tumor tissue is associated with PFS.

VI. To describe the toxicity associated with pazopanib in this patient population.

VII. To evaluate PFS and overall survival (OS). VIII. To compare, within patient, time to
tumor progression of 2nd-line therapy with time to tumor progression on pazopanib as 3rd-line
therapy.

OUTLINE:

Patients receive oral pazopanib hydrochloride once daily on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity. After completion of
study treatment, patients are followed up every 6 months.

Inclusion

- Histologically confirmed diagnosis of metastatic clear cell RCC

- At least one measurable lesion at baseline as per RECIST 1.1 criteria; if skin lesions
are reported as target lesions, they must be documented (at baseline and at every
physical exam) using color photography and a measuring device (such as a caliper) in
clear focus to allow the size of the lesion to be determined from the photograph

- 1 prior VEGF-TKI required

- 1 other prior systemic therapy allowed

- ECOG PS 0-1

- Resolution of grade >= 2 toxicity from prior therapy

- Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to comply with treatment and follow-up;
procedures conducted as part of the subject's routine clinical management (e.g., blood
count, imaging study) and obtained prior to signing of informed consent may be
utilized for screening or baseline purposes provided these procedures are conducted as
specified in the protocol

- A female is eligible to enter and participate in this study if she is of non-child
bearing potential (i.e., physiologically incapable of becoming pregnant), including
any female who has had (1) a hysterectomy, (2) a bilateral oophorectomy (ovariectomy),
(3) a bilateral tubal ligation, or (4) is post-menopausal; subjects not using hormone
replacement therapy (HRT) must have experienced total cessation of menses for >= 1
year and be greater than 45 years in age, OR, in questionable cases, have a follicle
stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40pg/mL (< 140
pmol/L); subjects using HRT must have experienced total cessation of menses for >= 1
year and be greater than 45 years of age OR have had documented evidence of menopause
based on FSH and estradiol concentrations prior to initiation of HRT

- Patients with childbearing potential, including any female who has had a negative
serum pregnancy test within 2 weeks prior to the first dose of study treatment,
preferably as close to the first dose as possible, and agrees to use adequate
contraception; GSK acceptable contraceptive methods, when used consistently and in
accordance with both the product label and the instructions of the physician, are as
follows: (1) complete abstinence from sexual intercourse for 14 days before exposure
to investigational product, through the dosing period, and for at least 21 days after
the last dose of investigational product, (2) oral contraceptive, either combined or
progestogen alone, (3) injectable progestogen, implants of levonorgestrel, estrogenic
vaginal ring, percutaneous contraceptive patches, intrauterine device (IUD) or
intrauterine system (IUS) with a documented failure rate of less than 1% per year, (4)
male partner sterilization (vasectomy with documentation of azoospermia) prior to the
female subject's entry into the study, and this male is the sole partner for that
subject, (6) double barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository); female subjects who are lactating should
discontinue nursing prior to the first dose of study drug and should refrain from
nursing throughout the treatment period and for 14 days following the last dose of
study drug

- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L

- Hemoglobin >= 9 g/dL (5.6 mmol/L)

- Platelets >= 100 X 10^9/L

- Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 X ULN

- Activated partial thromboplastin time (aPTT) =< 1.2 X ULN

- Total bilirubin =< 1.5 X ULN

- Alanine amino transferase (ALT) =< 2.5 X ULN

- Aspartate aminotransferase (AST) =< 2.5 X ULN

- Serum creatinine =< 2.0 mg/dL (133 umol/L) or, if >2.0 mg/dL; calculated creatinine
clearance (ClCR) by Cockroft-Gault formula >= 30 mL/min

- Urine Protein to Creatinine Ratio (UPC) < 1

Exclusion

- Concurrent use of other investigational agents

- Known history of allergic reactions to pazopanib or other VEGF-TKIs

- Presence of serious or uncontrolled infection

- Prior malignancy (Note: Subjects who have had another malignancy and have been
disease-free for 3 years, or subjects with a history of completely resected
non-melanomatous skin carcinoma or successfully treated in situ carcinoma are
eligible)

- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure
medication for 6 months prior to first dose of study drug; screening with CNS imaging
studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required
only if clinically indicated or if the subject has a history of CNS metastases

- Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to (1) active peptic ulcer
disease, (2) known intraluminal metastatic lesion/s with risk of bleeding, (3)
inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), (4) other
gastrointestinal conditions with increased risk of perforation, or (5) history of
abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28
days prior to beginning study treatment

- Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to (1) malabsorption syndrome or
(2) major resection of the stomach or small bowel

- Corrected QT interval (QTc) > 480 msecs using Bazett's formula

- History of any one or more of the following cardiovascular conditions within the past
6 months: (1) cardiac angioplasty or stenting, (2) myocardial infarction, (3) unstable
angina, (4) coronary artery bypass graft surgery, (5) symptomatic peripheral vascular
disease, or (6) Class III or IV congestive heart failure, as defined by the New York
Heart Association (NYHA)

- Poorly controlled hypertension defined as systolic blood pressure (SBP) of >= 140 mmHg
or diastolic blood pressure (DBP) of >= 90mmHg

- Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
study entry; BP must be re-assessed on two occasions that are separated by a minimum
of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from
each BP assessment must be < 140/90 mmHg in order for a subject to be eligible for the
study

- History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months;
(Note: subjects with recent DVT who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible)

- Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major)

- Evidence of active bleeding or bleeding diathesis

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels

- Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks prior to the
first dose of study drug

- Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
could interfere with subject's safety, provision of informed consent, or compliance to
study procedures

- Unable or unwilling to discontinue use of prohibited medications list as specified in
the full protocol for at least 14 days of a drug prior to the first dose of study drug
and for the duration of the study

- Treatment with any of the following anti-cancer therapies: (1) radiation therapy,
surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR
(2) chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal
therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the
first dose of pazopanib

- Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is
progressing in severity, except alopecia

- Non-Compliance: Patients, who in the opinion of the investigator, may not be able to
comply with the safety monitoring requirements of the study

- Medications that inhibit CYP3A4 may result in increased plasma pazopanib
concentrations; therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED
beginning 14 days prior to the first dose of study drug until discontinuation from the
study; strong CYP3A4 inhibitors include (but are not limited to): certain antibiotics
(including clarithromycin, telithromycin, and troleandomycin), certain HIV protease
inhibitors (including ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, and
lopinavir), certain antifungals (including itraconazole, ketoconazole, voriconazole,
and fluconazole) and certain antidepressants (including nefazodone)