Dose-defining Study of Tirapazamine Combined With Embolization in Liver Cancer

The study is a 3+3 design for dose escalation. Each cohort will have 3-6 patients based on
tolerability. Patients will receive escalated doses of tirapazamine until maximally tolerated
dose. Embolization is performed per standard practice using Lipiodol and Gelfoam under X-ray
guidance. Once a suitable dose is determined, an expansion cohort of 15 patients will be
treated with the recommended phase 2 dose to determine preliminary efficacy. Expansion
cohorts include (1) hepatocellular carcinoma, (2) metastatic solid tumors with liver
metastasis, and (3) neuroendocrine tumor. Adverse events are evaluated by CTCAE vs. 4.0 and
efficacy is evaluated by MRI using modified RECIST criteria and RECIST criteria.

- Confirmed diagnosis of HCC > 10 mm with a characteristic 4-phase CT or dynamic
contrast enhanced MRI finding showing intense arterial uptake followed by "washout" of
contrast in the venous-delayed phases per American Association for the Study of Liver
Disease (AASLD) criteria.

- Patients between ages 20 and 80

- Patients with single or multiple (2-4 nodules) HCC who are unsuitable or unwilling for
surgical resection or RFA. The largest tumor nodule should be less than 10 cm in the
largest diameter. The total volume of tumor cannot exceed 50% of liver; or patients
with liver metastatic gastrointestinal cancer, including neuroendocrine tumor

- Patients are candidates for TAE or Transarterial ChemoEmbolization (TACE). No tumor
invasion to portal vein or thrombosis in portal vein.

- ECOG score 0-1 with no known cardiac, pulmonary or renal dysfunction

- Child-Pugh score group A or B7 liver functional score

- Prior local therapies such as surgical resection, radiofrequency ablation, or alcohol
injection are allowed as long as tumor progresses from the prior treatment and the
patients are still candidates for TAE. All prior therapy must be at least 4 weeks
prior to enrollment and free from treatment-related toxicity.

- No TAE/TACE in the past

- Patients have normal organ function: ANC ≥ 1000 /µL, Hemoglobin ≥ 9 gm/dL, Platelets ≥
50,000 /µL, Creatinine ≤ 2 mg/dL, AST and ALT < 5 X upper normal limit of the current
institution; bilirubin ≤ 3.0 mg/dL, PT prolongation no more than 4 sec above upper
limit of normal.

For the expansion cohort of neuroendocrine tumor or metastatic gastrointestinal cancer

- Unresectable, locally advanced or metastatic, well differentiated (low or intermediate
grade), neuroendocrine tumors (NET).

- Liver metastatic gastrointestinal cancer.