Recombinant Human Endostatin Adenovirus Combined With Chemotherapy for Advanced Head and Neck Malignant Tumors

NCT ID: NCT02283489

Last Updated: 2014-11-05

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 180 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-31
• Study Completion Date: 2016-10-31

Brief Summary

This study will investigate the efficacy and safety of recombinant human endostatin adenovirus combined with chemotherapy for advanced head and neck malignant tumors.

Detailed Description

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.

In summary, this study will initially explore the efficacy and safety of recombinant human endostatin adenovirus combined with chemotherapy for advanced head and neck malignant tumors.

In the experimental group, the target lesion is defined as that injected by EDS01. In the control group, the target lesion is defined as that selected at the inception.

Conditions

Head and Neck Neoplasms

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Combination therapy A

Recombinant human endostatin adenovirus (EDS01), 5.0 × 1011 VP intratumorally on days 0 and 7; paclitaxel, 160 mg/m2 intravenously on day 1; cisplatin, 25 mg/m2 intravenously on days 1 to 3.

Group Type: EXPERIMENTAL

recombinant human endostatin adenovirus

Intervention Type: DRUG

Specification: 1mL/division, 1.0×1012 virus particle (VP). ESD01 preparation: Thaw at room temperature, dilute with normal saline to required volume (no more than 2 mL).

Method of administration: Intratumor injection, once a week for 2 weeks, every 3 weeks for one cycle. Select only one target lesion even when lesions are present. The target lesion is the largest and easiest to inject. This will be fixed during the study.

Cisplatin injection

Intervention Type: DRUG

Specification: 2ml: 10mg. Usage: 25mg/m2, days 1 to 3, according to instruction.

Paclitaxel injection

Intervention Type: DRUG

Specification: 5ml: 30mg. Usage: 160mg/m2 intravenously on day 1, according to instruction.

Combination therapy B

Recombinant human endostatin adenovirus (EDS01), 1.0 × 1012 VP intratumorally on days 0 and 7; paclitaxel, 160 mg/m2 intravenously on day 1; cisplatin, 25 mg/m2 intravenously on days 1 to 3.

Group Type: EXPERIMENTAL

recombinant human endostatin adenovirus

Intervention Type: DRUG

Specification: 1mL/division, 1.0×1012 virus particle (VP). ESD01 preparation: Thaw at room temperature, dilute with normal saline to required volume (no more than 2 mL).

Method of administration: Intratumor injection, once a week for 2 weeks, every 3 weeks for one cycle. Select only one target lesion even when lesions are present. The target lesion is the largest and easiest to inject. This will be fixed during the study.

Cisplatin injection

Intervention Type: DRUG

Specification: 2ml: 10mg. Usage: 25mg/m2, days 1 to 3, according to instruction.

Paclitaxel injection

Intervention Type: DRUG

Specification: 5ml: 30mg. Usage: 160mg/m2 intravenously on day 1, according to instruction.

Chemotherapy

Paclitaxel, 160 mg/m2 intravenously on day 1; cisplatin, 25 mg/m2 intravenously on days 1 to 3.

Group Type: EXPERIMENTAL

Cisplatin injection

Intervention Type: DRUG

Specification: 2ml: 10mg. Usage: 25mg/m2, days 1 to 3, according to instruction.

Paclitaxel injection

Intervention Type: DRUG

Specification: 5ml: 30mg. Usage: 160mg/m2 intravenously on day 1, according to instruction.

Interventions

recombinant human endostatin adenovirus

Specification: 1mL/division, 1.0×1012 virus particle (VP). ESD01 preparation: Thaw at room temperature, dilute with normal saline to required volume (no more than 2 mL).

Method of administration: Intratumor injection, once a week for 2 weeks, every 3 weeks for one cycle. Select only one target lesion even when lesions are present. The target lesion is the largest and easiest to inject. This will be fixed during the study.

Intervention Type: DRUG

Cisplatin injection

Specification: 2ml: 10mg. Usage: 25mg/m2, days 1 to 3, according to instruction.

Intervention Type: DRUG

Paclitaxel injection

Specification: 5ml: 30mg. Usage: 160mg/m2 intravenously on day 1, according to instruction.

Intervention Type: DRUG

Other Intervention Names

EDS01 (20140303)

Eligibility Criteria

Inclusion Criteria

• Advanced head and neck cancer unsuitable for surgery or radiotherapy (including head and neck squamous carcinoma and nasopharyngeal carcinoma, which should not more than 30%)
• Cytological and/or histopathologic diagnosis
• Target lesions can be treated with intratumor injection
• Lesions can be measured by imaging with a diameter of ≥2 cm (RECIST1.1)
• No chemotherapy, radiotherapy, or biotherapy administered in the past 4 weeks
• Age of 18 to 70 years
• Life expectation of ≥12 weeks
• ECOG performance status of 0 to 2
• Laboratory examinations performed ≤7 days before enrollment with the following results: absolute neutrophil count of ≥1.5 × 109 L-1, platelet count of ≥80 × 109/L, total bilirubin level of ≤2 mg/dL, AST and ALT levels of ≤2 times the upper limit of the reference range, and coagulation parameters ≤1.5 times the upper limit of the reference range
• Voluntary participation and written informed consent

Exclusion Criteria

• Allergy to EDS01
• Nerves and vessels passing through target lesions do not allow for injection of EDS01 into lesions
• Simultaneous radiation of target lesions
• Cancer recurrence within 6 months treated by paclitaxel
• Severe coagulation dysfunction and bleeding tendency
• Serious medical diseases, myocardial infraction in the past 3 months, or acute infection
• Currently pregnant or lactating
• Any conditions that the investigator regards as unsuitable for the study

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

West China Hospital

OTHER

Sponsor Role: collaborator

Renmiao Zhang

INDUSTRY

Sponsor Role: lead

Responsible Party

Renmiao Zhang

Project leader

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Renmiao Zhang, MD, PhD

Role: STUDY_DIRECTOR

Chengdu Shi Endor Biological Engineering Technology Co., Ltd

Locations

West China Hospital, Sichuan University

Chengdu, Sichuan, China

Site Status: RECRUITING

Sichuan Provincial People's Hospital

Chengdu, Sichuan, China

Site Status: RECRUITING

Chongqing Cancer Hospital

Chongqing, , China

Site Status: RECRUITING

Shanghai Ninth People's Hospital Affiliated Shanghai JiaoTong University School of Medicine

Shanghai, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Renmiao Zhang

Role: CONTACT

zrm_eds001@163.com

Facility Contacts

Liqun Zou, M.D.

Role: primary

Ke Xie, M.D.

Role: primary

Xiaohong Zhou, M.D.

Role: primary

Wei Guo, M.D.

Role: primary

Other Identifiers

ChengduShiEn_RMZ_001

Identifier Type: -

Identifier Source: org_study_id