DNA Vaccination Against Neuroblastoma

Relapsed Neuroblastoma Clinical Trial

Official title:

Pilot Clinical Study of DNA Vaccination Against Neuroblastoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04049864
• Other study ID #: BelarusianPediatric
• Status: Recruiting
• Phase: Early Phase 1
• Start date: January 9, 2019
• Est. completion date: December 31, 2023

Study information

• Verified date: March 2022
• Source: Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
• Contact: Alexander N Meleshko, PhD
• Phone: +375296940023
• Email: alexander.meleshko[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is pilot open-label study to evaluate the safety and immunogenicity of a DNA vaccine strategy in relapsed neuroblastoma patients following chemotherapy and HSC transplantation. The combined form of the vaccine includes an intramuscular injection of the DNA-polyethylenimine conjugate and oral administration using the attenuated Salmonella enterica as DNA vaccine carriers.

Objectives of the study:

1. To assess safety and document local and systemic toxicity to combined DNA vaccine

2. To determine immunogenicity of the vaccine

3. To evaluate clinical response to vaccination. Control of minimal residual disease in bone marrow and duration of remission.

Description:

DNA vaccine construction includes chimeric fusion of neuroblastoma-associated antigen and potato virus X coat protein (PVXCP) as an immune enhancer. In each course vaccine for one antigen is applies. The selection of antigens is carried out after analyzing of their expression in the tumor biopsy material by PCR and IHC. The list of antigens used in the study: tyrosine hydroxylase (TH), Phox2B, Survivin, MAGEA1, MAGEA3, PRAME. The antigens with the highest level of expression in the tumor sample of each patient are selected for vaccination.

Vaccination schedule for each patient includes three courses of vaccination. One course includes three administrations of vaccines against a single antigen. Vaccination is repeated at intervals of 1 week (plus minus 3 working days). Break between courses - 3-4 weeks. Each vaccination includes an injection and taking a capsule with a dose of bacteria.

For intramuscular injection, we use conjugate (polyplex) DNA with linear polyethylenimine 20 kDa (PEI). One dose includes 400 µg of DNA and 500 µg of PEI. When administered orally, the patient receives a suspension 10^10 CFU of an attenuated Salmonella enterica serovar typhimurium strain (SS2017) containing the plasmid of the corresponding DNA vaccine.

Before and during vaccination, an accompanying chemotherapy is carried out, including cyclophosphamide, propranolol, celecoxib and lenalidomide. Cyclophosphamide is prescribed three days before the start of each vaccination course in a single dose of 300 mg / m2. Lenalidomide is prescribed in a dose of 25 mg / day in a course of three weeks starting 7 days before the first vaccination course and ending on the day of the last vaccination course

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 20 Years

Eligibility

Inclusion Criteria:

1. The diagnosis of neuroblastoma recurrence with morphological / cytological confirmation;

2. The presence of tumor tissue for biopsy;

3. The absence of progression or a large tumor mass (bulky disease);

4. The physical status on the scale of ECOG 0 - 2.

5. Life expectancy of at least 12 months

6. Indicators of cellular immunity of the blood: lymphocytes - at least 1 * 10^9;

7. Availability of written informed consent of the patient and his parents (legal representatives) to participate in this protocol.

8. Compliance of parents (legal representatives) and the patient himself with participation in the study protocol.

Exclusion Criteria:

A. Based on the anamnesis:

1. The presence of any primary immunodeficiency;

2. The presence of a primary multiple malignant tumor;

3. The presence of autoimmune diseases in history (except thyroiditis);

4. Polyalgia;

5. Severe diseases, including those with severe symptoms, untreated inflammatory and infectious processes, due to which the patient cannot receive treatment in accordance with the study protocol.

6. Socioeconomic or geographical circumstances that cannot guarantee proper compliance with the requirements of the protocol for treatment and further observation.

B. based on survey data:

1. The absence of expression in the tumor tissue of two or more antigens used in the protocol;

2. The level of peripheral blood leukocytes <1.5 × 10^9 /L, platelet <50.0 × 10^9 /L, Hemoglobin less than 80 g / L;

3. Positive tests for human immunodeficiency virus (HIV), hepatitis B or C.

4. Severe impaired liver function - the levels of AST / SGOT or ALT / SGPT exceed the upper limit of normal 5 times or more.

Related Conditions & MeSH terms

• Neuroblastoma
• Relapsed Neuroblastoma

Intervention

Biological:
• DNA vaccine
conjugate of plasmid DNA with linear polyethylenimine 20 kDa (PEI) One dose includes 400 µg of DNA and 500 µg of PEI.
• Salmonella oral vaccine
suspension 10^10 CFU of an attenuated Salmonella enterica serovar typhimurium strain (SS2017) containing the plasmid of the corresponding DNA vaccine.

Drug:
• Lenalidomide
Lenalidomide is prescribed in a dose of 25 mg / day in a course of three weeks starting 7 days before the first vaccination course and ending on the day of the last vaccination course.

Locations

Country	Name	City	State
Belarus	Belarussian Research Center for Pediatric Oncology, Hematology and Immunology	Minsk	Minsk Region

Sponsors (1)

Lead Sponsor	Collaborator
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology

Country where clinical trial is conducted

Belarus, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events experienced by subjects	To assess the safety of the DNA-PEI and Salmonella vaccines	for 3 months from the first vaccination
Primary	Immune response to the vaccine	Immunogenicity will be evaluated by assessing T-cell IFN-? production in ELISPOT and PVXCP antibody production by ELISA	In check point after 2nd course (9 week after first vaccine)
Primary	Immune response to the vaccine	Immunogenicity will be evaluated by assessing T-cell IFN-? production in ELISPOT and PVXCP antibody production by ELISA	In check point after 3rd course (14 week after the first vaccine)
Primary	Minimal residual disease - MRD	MRD in bone marrow measured by RQ-PCR and flow cytometry	up to 4 weeks after the last vaccination
Secondary	Progression free survival - PFS	Time from treatment to date of first documented progression or date of death	Up to 12 months