Study of TH-302 Monotherapy as Second-line Treatment in Advanced Biliary Tract Cancer

Biliary Tract Cancer Clinical Trial

Status Completed

Clinical Trial Summary

Biliary tract cancer is relatively rare cancer, with generally poor prognosis. In metastatic/recurrent biliary tract cancer, the most commonly used 1st-line chemotherapy is gemcitabine+cisplatin combination. However, there is no standard 2nd-line chemotherapy and there is no validated targeted therapeutic agent, even though this tumor harbors diverse genetic characteristics.

TH-302 (1-methyl-2-nitro-1H-imidazole-5-yl)methyl N,N'-bis(2-bromoethyl) diamidophos-phate is a nitroimidazole-linked prodrug of a brominated version of isophosphoramide mustard (Br-IPM). When exposed to hypoxic conditions, TH-302 is reduced at the nitroimadazole site of the prodrug by intracellular reductases leading to the release of Br-IPM. Br-IPM can then act as a DNA crosslinking agent. In areas of normoxia, TH-302 remains intact as a prodrug and toxicity is minimized. In addition, preclinical data suggest that after activation, the active moiety may diffuse to areas outside the hypoxic region, demonstrating a "bystander" effect and possibly exhibiting additional anti-tumor activity.

It is well known that biliary tract cancer is hypovascular tumor, so it contains large hypoxic area in the tumor. Therefore it would be worthy to test TH-302 in biliary tract cancer.

This study is a phase II study of TH-302 monotherapy as second-line treatment in advanced biliary tract cancer, to investigate efficacy and safety of TH-302 monotherapy.

Clinical Trial Description

Biliary tract cancer is relatively rare disease worldwide among all kinds of solid tumors. However the incidence of biliary tract cancer is relatively higher in Korea compared to the western countries. The prognosis of all biliary tract cancer is poor, that is, the 5-year overall survival rate is 26.7%. The main reasons of poor prognosis are: 1) there is no screening method to detect in early stage, 2) the relapse rate after curative surgery is high, 3) in metastatic/recurrent biliary tract cancer, the chemo-sensitivity is relatively low. And another important reason of poor prognosis is low interest of investigators. So the researches with new agents have been limited compared with other types of cancer such as lung cancer, breast cancer and colon cancer etc. In metastatic/recurrent biliary tract cancer, the available cytotoxic chemotherapies are composed of gemcitabine, cisplatin, 5-FU, etc. The most commonly used 1st-line chemotherapy is gemcitabine+cisplatin combination. (N Engl J Med 2010; 362 (14): 1273-81) There is no standard 2nd-line chemotherapy so far.

The overall survival with these cytotoxic chemotherapies is about 8-10 months. So far, there is no validated targeted therapeutic agent in biliary tract cancer, even though this tumor harbors diverse genetic characteristics.

Therefore, there is a huge unmet medical need in biliary tract cancer.

TH-302 (1-methyl-2-nitro-1H-imidazole-5-yl)methyl N,N'-bis(2-bromoethyl) diamidophos-phate is a nitroimidazole-linked prodrug of a brominated version of isophosphoramide mustard (Br-IPM). When exposed to hypoxic conditions, TH-302 is reduced at the nitroimadazole site of the prodrug by intracellular reductases leading to the release of Br-IPM. Br-IPM can then act as a DNA crosslinking agent. Tumors often consist of large areas of highly hypoxic regions that are known to be resistant to chemotherapy and radiation treatment. In areas of normoxia, TH-302 remains intact as a prodrug and toxicity is minimized. Thus, TH-302 has been designed to target these highly hypoxic tumor regions and this makes it an attractive candidate for clinical development. In addition, preclinical data suggest that after activation, the active moiety may diffuse to areas outside the hypoxic region, demonstrating a "bystander" effect and possibly exhibiting additional anti-tumor activity.

It is well known that biliary tract cancer is hypovascular tumor, so it contains large hypoxic area in the tumor. Therefore it would be worthy to test TH-302 in biliary tract cancer.

This study is a phase II study of TH-302 monotherapy as second-line treatment in advanced biliary tract cancer. ;

Related Conditions & MeSH terms

• Biliary Tract Cancer
• Biliary Tract Neoplasms

• NCT number: NCT02433639
• Study type: Interventional
• Source: Seoul National University Hospital
• Status: Completed
• Phase: Phase 2
• Start date: April 2015
• Completion date: October 2017