Trial Information

A Phase II Protocol of Arsenic Trioxide (Trisenox) in Subjects With Advanced Primary Carcinoma of the Liver

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed malignancies in some
regions of the world, particularly Africa and the Asian portion of the Pacific rim.
However, it is an uncommon malignancy in the United States, with less than 14,000 cases
diagnosed annually. Malignancies of the gallbladder and biliary tree are also uncommon. As
with most solid tumors, unless either neoplasm can be resected completely, the prognosis is
grim. A variety of agents have been utilized in the therapy of HCC and cholangiocarcinoma,
both as single agents and in combination regimens. However, despite response rates which
exceed 50% when hepatic arterial therapy is utilized for HCC, response rates for
cholangiocarcinoma and for systemic treatment of HCC are considerably lower. Long term
survival remains uncommon. For this reason, new therapeutic approaches must be evaluated.

Trisenox (arsenic trioxide) is a newly-approved pharmaceutical grade arsenic compound
antineoplastic agent which has demonstrated clear activity in anthracycline- and all-trans
retinoic acid-resistant acute promyelocytic leukemia. Trisenox also has US Compendium
listing for acute leukemia, chronic myelogenous and lymphocytic leukemias, myelodysplasia,
multiple myeloma, and hepatocellular carcinoma (HCC). Similar to the taxanes and vinca
alkaloids, Trisenox appears to interfere with microtubule function, which triggers cell
differentiation, and induces programmed death, or apoptosis. The mechanism of this is
unclear, but appears to involve activation of caspases and the down-regulation of the BCL-2
oncogene. Trisenox also interfere with the function of NF-kappaB, leading to inhibition of
cellular proliferative signals, apoptosis, and inhibition of tumor angiogenesis.

Trisenox was shown to be effective in a pivotal trial consisting of 40 subjects, ages 5 to
72, at a nine-institution multi-center trial led by Memorial Sloan-Kettering Cancer Center.
With Trisenox, 70% of the subjects achieved a complete remission, and 79% of the complete
responders achieved a molecular remission as measured by reverse transcriptase-polymerase
chain reaction (RT-PCR). Complete remission was achieved on average within two months after
initiation of Trisenox. Sixty-eight percent of subjects who achieved complete remission were
still alive and 58% were disease free, at a median follow-up time of 16 months.

To date, an optimal dose and schedule of Trisenox has not yet been defined. This agent has
been administered on daily, twice a week, and weekly doses. As there is no evidence that
one regimen is clearly superior to any other, for the sake of convenience, participants on
this trial will receive Trisenox on the weekly schedule. Administration of chemotherapy on a
weekly schedule is commonly utilized across a broad spectrum of regimens and tumor types. On
this trial, subjects will receive a dose of intravenous Trisenox 0.35 mg/kg on days 1, 8,
15, and 22 over two hours. Each cycle will be 28 days in length. Subjects will receive two
treatment cycles (8 weeks) and then undergo objective radiographic tumor assessments. On
this study, subjects may receive up to a maximum of 12 such treatment cycles. As the outlook
for subjects with advanced primary liver cancer is so poor, new regimens and treatment
strategies must be evaluated.