The growth and metastasis of solid tumors are dependent on angiogenesis. Endostatin, the C-terminal proteolytic fragment of collagen XVIII, is an effective endogenous angiogenesis inhibitor in cancer therapy in mice. Applied for clinical studies in solid tumor, however, recombinant human endostatin protein, difficulties in a large-scale production of the recombinant endostatin protein, and the cumbersome daily administration. Up to now, its clinical application has been hampered by those matters. We herein constructed a adenoviral vector ecoding human endostatin. This study will test the safety and efficacy of recombinant human endostatin adenovirus (Ad-rhE) in the treatment of patients with advanced solid tumors.

NCT00262327

Conditions

1. Advanced Solid Tumor

Interventions

1. Drug: Antangiogenesis
2. Genetic: endostatin gene

MeSH:Neoplasms

HPO:Neoplasm

Expression of endostatin by adenoviral gene transfer (Ad-rhEndo, E10A) generates a strong systemic therapeutic effect in several models of solid tumors in mice.7,8,9,10 --- E10A ---

Intratumoral injections of E10A into subcutaneous xenografts of hepatocellular carcinoma BEL-7402, nasopharyngeal carcinoma CNE-2, Tongue cancer Tca8113 in nude mice demonstrated significant tumor growth inhibition and reduce angiogenesis in tumors. --- E10A ---

No toxic effects of E10A administration in these pharmacology studies were identified. --- E10A ---

On the base of promising preclinical results in solid tumors, we undertook a dose-escalation phase I trial of E10A in the treatment of patients with advanced solid tumors. --- E10A ---

Angiogenesis, the formation of new blood vessel from existing vessels, is essential for tumor growth and metastasis. Antiangiogenic therapies inhibit the growth of genetically stable endothelial cells, and most tumors should starve to death with little acquired resistance. Endostatin has been shown to block endothelial cell proliferation, survival, and migration. Antitumor activity of endostatin protein has been demonstrated in various murine and human tumors in animal model studies without any detectable toxicity. Endostatin gene therapy could directly express the highly bioactive protein in vivo by means of the mechanism of eukaryotic expression system as post-translational modification and folding, as well as overcoming the challenge of the long-term storage and the cumbersome daily administration of endostatin protein. E10A is a replication-deficient recombinant adenovirus containing a wild-type human endostatin transgene constructed from serotype 5 adenovirus (Ad5). Preclinical studies demonstrated that intratumoral injection of E10A provided significant tumor growth inhibition and sustained elevation of endostatin in blood and tumor tissue in hepatocellular carcinoma, nasopharyngeal carcinoma, and tongue cancer animal models. A Phase I clinical trial of E10A we conducted showed that repetitive intratumoral injection of E10A resulted in a small and sustained elevation of endostatin in blood and had a mild antitumor activities with very limited toxicity. The major toxicity was transient and manageable fever. A randomized Phase III trial in nonsmall-cell lung cancer showed endostatin improved response rate and time to tumor progression in combination to chemotherapy. Therefore, we designed a randomized phase II trial to explore the safety and effectiveness of E10A combined with chemotherapy in the treatment of patients with head and neck cancer.

NCT00634595

Conditions

1. Head and Neck Squamous Carcinoma
2. Nasopharyngeal Carcinoma

Interventions

1. Drug: E10A
2. Drug: Cisplatin
3. Drug: Paclitaxel

MeSH:Carcinoma Head and Neck Neoplasms Nasopharyngeal Carcinoma Carcinoma, Squamous Cell

HPO:Carcinoma Neoplasm of head and neck Squamous cell carcinoma

A Randomized Phase II Clinical Trial of an Adenovirus-mediated Endostatin Gene (E10A) Combined With Cisplatin and Paclitaxel in Patients With Head and Neck Cancer. --- E10A ---

Trial of E10A in Head and Neck Cancer Angiogenesis, the formation of new blood vessel from existing vessels, is essential for tumor growth and metastasis. --- E10A ---

E10A is a replication-deficient recombinant adenovirus containing a wild-type human endostatin transgene constructed from serotype 5 adenovirus (Ad5). --- E10A ---

Preclinical studies demonstrated that intratumoral injection of E10A provided significant tumor growth inhibition and sustained elevation of endostatin in blood and tumor tissue in hepatocellular carcinoma, nasopharyngeal carcinoma, and tongue cancer animal models. --- E10A ---

A Phase I clinical trial of E10A we conducted showed that repetitive intratumoral injection of E10A resulted in a small and sustained elevation of endostatin in blood and had a mild antitumor activities with very limited toxicity. --- E10A ---

A Phase I clinical trial of E10A we conducted showed that repetitive intratumoral injection of E10A resulted in a small and sustained elevation of endostatin in blood and had a mild antitumor activities with very limited toxicity. --- E10A --- --- E10A ---

Therefore, we designed a randomized phase II trial to explore the safety and effectiveness of E10A combined with chemotherapy in the treatment of patients with head and neck cancer. --- E10A ---

Recombinant human endostatin adenovirus injection is a novel anti-tumor gene therapy drug. E10A contains a recombinant human endostatin gene with the second-generation recombinant adenovirus as its vector. After transfection tumor cells. E10A expresses human endostatin, which inhibits vascular endothelial cell proliferation and tumor angiogenesis, and blocks tumor blood supply, thereby specifically inhibiting tumor growth and inducing apoposis of tumor cells. Both pre-clinical and animal models have demonstrated the anti-tumor activities of E10A. The safety and efficacy of E10A in treating head and neck cancer has also been demonstrated in Phase I and Phase II studies.

NCT02630264

Conditions

1. Head and Neck Neoplasms

Interventions

1. Drug: Endostatins
2. Drug: Paclitaxel injection
3. Drug: Cisplatin injection

MeSH:Carcinoma, Squamous Cell Squamous Cell Carcinoma of Head and Neck Head and Neck Neoplasms

HPO:Neoplasm of head and neck Squamous cell carcinoma

A Randomized, Open-label, Multi-center Phase III Study Designed to Evaluate the Safety and Efficacy of E10A in Patients With Recurrent/Unresectable Squamous Cell Carcinoma of the Head and Neck Region. --- E10A ---

E10A for the Treatment of Squamous Cell Carcinoma of the Head and Neck Recombinant human endostatin adenovirus injection is a novel anti-tumor gene therapy drug. --- E10A ---

E10A contains a recombinant human endostatin gene with the second-generation recombinant adenovirus as its vector. --- E10A ---

E10A expresses human endostatin, which inhibits vascular endothelial cell proliferation and tumor angiogenesis, and blocks tumor blood supply, thereby specifically inhibiting tumor growth and inducing apoposis of tumor cells. --- E10A ---

Both pre-clinical and animal models have demonstrated the anti-tumor activities of E10A. --- E10A ---

The safety and efficacy of E10A in treating head and neck cancer has also been demonstrated in Phase I and Phase II studies. --- E10A ---

All adverse events were recorded regardless of their relevance to E10A. --- E10A ---

3. Patients were required to have at least one measurable (by imaging or photograph complied RECIST) lesion with the largest diameter ≧2 cm and suitable for the intratumoral injection of E10A, 4. --- E10A ---

Recent history of myocardial infarction acute infection, pregnancy or lactation, or symptomatic brain metastases 7. A history of corticosteroids or immunosuppressives use within four weeks of study entry 8. Received any chemotherapy or radiotherapy within four weeks of study entry Head and Neck Neoplasms Carcinoma, Squamous Cell Squamous Cell Carcinoma of Head and Neck Head and Neck Neoplasms Phase II Clinical Study From March 2008 to December 2010 Safety and efficacy of intratumoral injections of E10A to cisplatin and paclitaxel was evaluated a multicenter, open-label, randomized clinical study in patients with advanced head and neck squamous cell carcinoma. --- E10A ---

Patients with locally advanced or metastatic head and neck squamous cell carcinoma or nasopharyngeal carcinoma not suitable for operation or radiotherapy were randomly assigned to receive E10A plus chemotherapy every 21 for a maximum of six cycles or to receive chemotherapy only. --- E10A ---

The administration of E10A benefited some subgroups of patients. --- E10A ---

In the HNSCC patients, the objective RR was 36.5% (15/41) with E10A administration, exhibiting a trend of exceeding the rate of 20.0% (7/35) in the control group (P = 0.090; OR: 0.43), whereas the objective RR was 44.4% (12/27) versus 40.6% (13/32) in the NPC patients (P = 0.487; OR: 0.86). --- E10A ---

Patients who had previously received chemotherapy in the E10A group had a 44.8% (12/29) objective RR, whereas patients in the control group had only a 22.6% objective RR (7/31; P = 0.06, OR: 0.36). --- E10A ---

The difference in the Kaplan-Meier estimates of PFS favored chemotherapy plus E10A, which resulted in a 3.43-month improvement. --- E10A ---

in the E10A group. --- E10A ---

The OS of the E10A group was relatively prolonged in different subgroups compared with the controls (e.g., 13.37 months versus 9.67 months in the HNSCC patients, 13.03 months versus 10.50 months in those who had received prior treatment; Figure 1), but these results did not translate into significantly superior survival. --- E10A ---