TH-302 Plus Doxorubicin Delivered by Trans-Arterial Chemoembolization (TACE) in Patients With Hepatocellular Carcinoma

Transarterial chemoembolization (TACE) is the major modality utilized for tumor downstaging
for transplant and for local therapy in non-transplant patients. This procedure allows
delivery of concentrated drugs to the tumor, followed by embolization that eliminates its
blood supply creating an environment of hypoxia. The process induces tumor ischemia, while
achieving a drug concentration in the tumor 10 to 25 times greater than can be achieved by
infusion.

A hypoxic microenvironment is a characteristic of many solid tumors including hepatocellular
cancer, further induced by TACE. The hypoxia-activated prodrug, TH-302, is designed to
selectively physiologically target the hypoxic microenvironment. While doxorubicin and
cisplatin have been used as the drugs in TACE among other agents, none have stood out as the
optimal agent in targeting HCC. Because of the action of TH-302 in hypoxia, this agent has a
mechanistic advantage as a agent in TACE.

The current study is designed to assess the potential therapeutic benefit of adding TH-302
to the standard doxorubicin based TACE regimen in patients with advanced hepatocellular
carcinomas.

Inclusion Criteria:

- At least 18 years of age

- Ability to understand the purposes and risks of the study and has signed a written
informed consent form approved by the investigator's IRB/Ethics Committee

- Patients with hepatocellular carcinoma with either:

1. liver limited disease who are not transplant candidates as they fall outside of
Milan criteria, but may be eligible for transplant after successful downstaging
with TACE

2. liver limited disease who satisfy Milan criteria, but are at risk of falling out
of Milan criteria before they receive a liver transplant

3. non-transplantable HCC but with liver limited or metastatic disease that
requires local TACE therapy

- Measurable disease by modified RECIST criteria (at least one target lesion outside of
previous radiation fields)

- ECOG performance status of 2 or less

- Life expectancy of at least 3 months

- Childs-Pugh Class A or B

- HCC amenable to TACE

- Patent main portal vein (thrombosis of portal vein branch not exclusionary)

- Acceptable liver function:

- Bilirubin < 2 mg/dL

- AST (SGOT) and ALT (SGPT) < 5 x ULN is allowed

- Acceptable renal function:

- Serum creatinine < 1.5 ULN

- Acceptable hematologic status (without hematologic support for TACE #1):

- ANC > 500 cells/μL

- Platelet count > 50,000/μL

Exclusion Criteria:

- New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial
infarction within 6 months prior to Day 1, unstable arrhythmia or symptomatic
peripheral arterial vascular disease

- Known brain, leptomeningeal or epidural metastases (unless treated and well
controlled for >=3 months)

- Previously treated malignancies, except for adequately treated non-melanoma skin
cancer, in situ cancer, or other cancer from which the subject has been disease-free
for at least 5 years

- Severe chronic obstructive or other pulmonary disease with hypoxemia (requires
supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse
oximetry after a 2 minute walk) or in the opinion of the investigator any
physiological state likely to cause systemic or regional hypoxemia

- Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without
complete recovery

- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy

- Sorafenib within the previous 4 weeks or the intention to initiate sorafenib while on
study

- Poor liver function as indicated by serum bilirubin > 2 mg/dL, Child-Pugh Class C,
severe coagulopathy (INR > 2) not correctable with vitamin K, or active hepatic
encephalopathy

- Main portal vein occlusion

- Liver rupture or tumor penetration of liver capsule

- Tumor invasion of biliary system with biliary obstruction

- Severe cytopenias, including ANC < 500 cells/μL, Hemoglobin < 8 g/dL, or platelets <
50,000/μL

- Subjects who have exhibited allergic reactions to a structural compound, biological
agent similar to TH-302

- Females who are pregnant or breast-feeding

- Concomitant disease or condition that could interfere with the conduct of the study,
or that would, in the opinion of the investigator, pose an unacceptable risk to the
subject in this study

- Unwillingness or inability to comply with the study protocol for any reason