Recombinant Human Endostatin Adenovirus Combined With Chemotherapy for Advanced Head and Neck Malignant Tumors: Phase II, Multicenter, Randomized, Controlled Clinical Trial

Head and neck cancer is one of the most common malignant tumors in China, accounting for 19.9% to 30.2% of malignant tumors in this country. Approximately 60% to 70% of patients have stage III or IV disease at the time of diagnosis, and the 5-year overall survival is about 30%. The local recurrence rate ranges from 50% to 60%. The 5-year overall survival for patients treated with multidisciplinary treatment, which is a common treatment method that includes surgery, chemotherapy, radiotherapy, and biotherapy, has recently increased by 5%. Further improvements in the treatment effects of head and neck cancer are required.

Endostatin, an endogenous angiogenesis inhibitor and a C-terminal fragment of collagen XVIII, effectively inhibits tumor angiogenesis by specific inhibition of neovascular endothelial cells [7, 8]. Its characteristic antitumor effect is dose-dependent, requiring continuous high protein activity. Transportation of recombinant genes with adenovirus vectors into the body leads to continuous expression of high levels of endogenous secretory proteins, resolving the limitation of foreign protein infusion. Previous studies have shown that the antitumor activity of recombinant human endostatin adenovirus is higher than that of recombinant human endostatin protein.

EDS01, an antitumor gene therapy product that uses recombined adenovirus type 5 as the vector for the human endostatin gene, may be termed a recombinant adenovirus-recombined human endostatin gene. Intratumor injection of EDS01 reportedly results in transportation of the human endostatin gene into tumor cells by adenovirus infection, leading to the expression of endostatin protein. Expression of this protein inhibits neovascular endothelial cells, neovascularization, and tumor growth and metastasis. Both in vivo and in vitro experiments have shown that EDS01 significantly inhibits the growth of neovascular endothelial cells and tumor growth in nude mouse xenograft models of laryngocarcinoma and nasopharyngeal carcinoma.

A phase I clinical trial (No. treatment effect) conducted at West China Hospital of Sichuan University enrolled patients with superficial advanced head and neck cancer lesions. The patients underwent injection of different doses of EDS01, and the investigators performed a preliminary evaluation of the maximally tolerated dose and adverse events. The study showed that, whether administered by dose escalation or in multiple doses, EDS01 was well tolerated without dose-limiting toxicity and maximum tolerated dose. The main side effects were fever and injection site pain with flu-like symptoms. A small amount of EDS01 (1/10 000 000) was absorbed into the bloodstream. A thimbleful (1/100 000 000 to 1/10 000 000 000) was excreted in the urine and feces and was nontoxic to the environment. The target lesions exhibited a treatment response.

According to the results of this phase I trial, both 5.0 × 1011 and 1.0 × 1012 virus particles (VP) of EDS01 showed adequate safety and treatment responses. Therefore, in the subsequent phase II clinical trial, the optimal of these two doses will be determined. The treatment effects and safety of this protocol for head and neck cancer will also be further investigated.