Pazopanib Hydrochloride and Bevacizumab in Treating Patients With Previously Untreated Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. To determine the safe phase II dose of this novel regimen. (Phase I) II. To determine the
median progression free survival (PFS) from this novel regimen. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety and toxicity of the proposed regimen. (Phase I) II. To evaluate the
response rate. (Phase I) III. To evaluate the pharmacokinetics of pazopanib (pazopanib
hydrochloride). (Phase I) IV. To evaluate the vascular endothelial growth factor (VEGF)
levels and myeloid derived suppressor cell (MDSC) levels at various time points and correlate
with response. (Phase I) V. To evaluate the safety and toxicity of this new regimen. (Phase
II) VI. To evaluate the VEGF levels, interleukin (IL)-8 levels and MDSC levels at various
time points and correlate with outcome. (Phase II) VII. To evaluate the PFS rate at 12
months. (Phase II) VIII. To evaluate overall survival. (Phase II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive pazopanib hydrochloride orally (PO) on days 1-28, and bevacizumab
intravenously (IV) over 30-90 minutes on days 36 and 50. Courses repeat every 70 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Biopsy/pathology-proven clear cell renal cell carcinoma (CCRCC) with metastases

- Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Hemoglobin >= 10 gm/dL

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

- Platelets >= 100 x 10^9/L

- Total bilirubin =< upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< ULN

- International normalization ratio (INR) and activated partial thromboplastin time
(aPTT) < 1.2 x ULN

- Serum creatinine < 1.5 mg/dL or if serum creatinine > 1.5 mg/dL then calculate
creatinine clearance (CrCL) > 30 mL/min

- Urine protein to creatinine ratio =< 1 (if urine protein creatinine ratio is > 1, then
a 24-hour urine total protein must be assessed; subjects will be ineligible if the
24-hour urine protein is found to be > 1 gm)

- Normal cardiac ejection fraction (> 50%) by multi gated acquisition scan (MUGA) or
echocardiogram

- Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria present

- Ability to swallow and retain oral medication

- Subjects of child-bearing potential must agree to use adequate contraceptive methods
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry
and for the duration of study participation; should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately

- Subject or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Subjects with known brain metastases should be excluded from this clinical trial

- Prior VEGF targeted therapies for renal cell carcinoma (RCC) including adjuvant or
neoadjuvant treatments; in phase 1 only, one prior therapy with high dose IL-2 or
anti-programmed cell death (PD)-1 compound alone or in combination with cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) targeting drug is allowed on the trial

- Subjects diagnosed with another cancer in the past 3 years; excluding basal cell
carcinoma or squamous cell carcinoma, of skin which were completely cured by resection

- Concurrent use of another anti-cancer drug including an investigational anti-cancer
agent

- Major surgery within 28 days prior to treatment or major surgery planned during the
next 6 months

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic or psychiatric illness/social situations that would limit
compliance with study requirements

- History of any of the following cardio-vascular condition:

- Myocardial infarction (MI)

- Unstable angina

- Coronary artery bypass grafting (CABG)

- Coronary angioplasty or stenting

- Symptomatic peripheral arterial disease (PAD)

- History of symptomatic chronic congestive heart failure (CHF)

- History of cerebrovascular accidents including transient ischemic attacks (TIA)

- Corrected QT interval (QTc) > 480 msec

- Uncontrolled hypertension (systolic blood pressure [BP] > 150 mm Hg or diastolic
BP of > 90 mm Hg); if the screening BP is elevated, adjustments in
anti-hypertensives are permitted and a re-screening will be permitted for BP
assessment with three consecutive values obtained 2 minutes apart; the 3 values
have to be below 150/90 mm Hg for eligibility and can only be obtained after 2
days of the last change in anti-hypertensive medication; use of clonidine is not
permissible for adjusting the BP during this period

- History of deep vein thrombosis (DVT) or pulmonary embolism (PE) in the past 6 months

- Subjects should not have packed red blood cells (PRBC) or platelet transfusion within
14 days of the screening

- Evidence of active bleeding or bleeding disorder

- Subjects currently on anti-coagulation therapy are not eligible

- Unable to discontinue the use of prohibited medications

- Pregnant or nursing female subjects

- Unwilling or unable to follow protocol requirements

- Any condition which in the investigator's opinion deems the subject an unsuitable
candidate to receive study drug

- Received an investigational agent within 30 days prior to enrollment