Clinical trial NCT04049864: DNA Vaccination Against Neuroblastoma
Official title: Pilot Clinical Study of DNA Vaccination Against Neuroblastoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: EARLY_PHASE1
Conditions: Relapsed Neuroblastoma
Keywords: neuroblastoma
DNA vaccine
Salmonella vaccine
polyethylenimine
Lead sponsor: Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
Sponsor class: OTHER
First posted: 2019-08-08
Enrollment: 12
Sex: ALL
Minimum age (years): 1
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Adverse events experienced by subjects
timeFrame: for 3 months from the first vaccination
measure: Immune response to the vaccine
timeFrame: In check point after 2nd course (9 week after first vaccine)
measure: Immune response to the vaccine
timeFrame: In check point after 3rd course (14 week after the first vaccine)
measure: Minimal residual disease - MRD
timeFrame: up to 4 weeks after the last vaccination
Secondary outcomes:
measure: Progression free survival - PFS
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Minsk
country: Belarus
facility: Belarussian Research Center for Pediatric Oncology, Hematology and Immunology
state: Minsk Region
Study officials:
affiliation: Belarussian Research Center for Pediatric Oncology, Hematology and Immunology
name: Inna V Proleskovskaya, PhD, MD
role: STUDY_DIRECTOR
References: