Tivozanib in Treating Patients With Liver Cancer That Is Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. Progression free survival (PFS) at 24 weeks in patients with advanced hepatocellular
carcinoma (HCC).

SECONDARY OBJECTIVES:

I. To determine the safety of tivozanib in HCC. II. To determine the overall survival (OS)
and clinical benefit rate (complete response [CR], partial response [PR] and stable disease
[SD]) by Response Evaluation Criteria in Solid Tumors (RECIST).

III. To determine the steady state pharmacokinetics (PK) and soluble vascular endothelial
growth factor receptor 2 (VEGFR-2) baseline/change with tivozanib and use modeling to
correlate exposure with biomarker change and the primary outcome measure of PFS.

IV. To determine the change in viral load (hepatitis B virus [HBV] and hepatitis C virus
[HCV]) during therapy in patients with HBV or HCV associated HCC.

V. To determine the change in tumor marker (alfa fetoprotein) with tivozanib therapy is in
the effect of tivozanib on several tumor-associated immune response markers.

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

Patients receive tivozanib orally (PO) once daily (QD) on days 1-21. 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 Criteria:

- Advanced staged HCC (unresectable and not amenable to local or regional therapy; or
metastatic HCC); the diagnosis of HCC should be based on at least one of the
following:

- Magnetic resonance imaging (MRI) or computed tomography (CT) consistent with
liver cirrhosis AND at least one solid liver lesion measuring >= 2 cm, with
characteristics arterial enhancement and venous washout regardless of
alpha-fetoprotein (AFP) levels

- AFP >= 400 ng/mL AND evidence of at least one solid liver lesion >= 2 cm
regardless of specific imaging characteristics on CT or MRI

- Histological/cytology biopsy confirming HCC

- Patients must have measurable disease per RECIST 1.1 criteria defined as at least one
lesion that can be accurately measured in at least one dimension, and that has not
been the target of local or regional therapy including transarterial
chemoembolization, intra-arterial chemotherapy, ethanol or radiofrequency ablation

- Life expectancy of greater than 3 months

- Child-Pugh liver function class A

- Aspartate aminotransferase (AST) =< 5 x institutional upper limits of normal (ULN)

- Total bilirubin =< 3 mg/dL

- International normalized ratio (INR) =< 2.0 (unless due to therapeutic warfarin use)

- Serum albumin > 2.8 g/dL

- Creatinine =< 1.5 x institutional ULN

- Absolute neutrophil count (ANC) >= 1200/mm^3

- Platelets >= 60,000/mm^3

- Hemoglobin (Hgb) >= 8.5 g/dL

- Patients must not have any evidence of bleeding diathesis or active gastrointestinal
bleeding

- Patients must not be known to be human immunodeficiency virus (HIV) positive

- Patients must not have other uncontrolled intercurrent illnesses (excluding HBV or
HCV); this includes (but is not limited to) ongoing or active infection, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements

- Sexually active fertile patients (male and female), and their partners, must agree to
use medically accepted methods of contraception during the course of the study and for
3 months after the last dose of the study drug

- Female patients of childbearing potential must have a negative pregnancy test at
screening

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

- 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:

- Patients who have had prior anti-angiogenic therapy, including but not limited to
sorafenib, brivanib, bevacizumab, or sunitinib

- Patients who have had any prior line of systemic therapy including cytotoxic agents or
molecularly targeted agents for advanced/unresectable disease; any number of prior
regional therapies with transarterial chemoembolization (TACE), brachytherapy with
yttrium-90 microsphere, intra-arterial chemotherapy, surgery, or ablative therapy are
allowed

- Prior liver transplantation and on immunosuppression

- Known symptomatic or uncontrolled brain metastases or epidural disease

- Patient has a corrected QT interval (QTcF) > 500 ms at screening

- The patient is unable to swallow pills or diagnosed with a gastrointestinal disorder
that are likely to interfere with the absorption of the study drug or with the
patient's ability to take regular oral medication

- The patient is pregnant or breastfeeding

- Patients with second primary cancer (except adequately treated nonmelanoma skin
cancer, curatively treated in-situ carcinoma of the cervix or superficial bladder
cancer, or other solid tumors including lymphoma without bone marrow involvement
curatively treated with no evidence of disease for >= 5 years)

- The patient has a previously-identified allergy or hypersensitivity to components of
the study treatment formulation

- Patients receiving any medications or substances that are strong inducers of
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible;
moderate inducers of CYP3A4 should be used with caution

- Urine protein: creatinine ratio > 1