Neoepitope-based Personalized DNA Vaccine Approach in Pediatric Patients With Recurrent Brain Tumors

Study Overview
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Brief Summary
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The purpose of this research study is to learn about the safety and feasibility of giving a personalized DNA vaccine to people with brain tumors that have returned or have been resistant to treatment.

Official Title
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A Pilot Study to Assess the Safety, Feasibility, and Preliminary Efficacy of a Neoepitope-based Personalized DNA Vaccine Approach in Pediatric Patients With Recurrent Brain Tumors

Conditions
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Pediatric Recurrent Brain Tumor

Intervention / Treatment
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* Biological: Personalized neoantigen DNA vaccine
* Device: Ichor TDS-IM v2.0
* Procedure: Peripheral blood draw


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria for Tissue Sequencing (Step 1) Inclusion Criteria: Any patient between the ages of 12 and 39 years of age (inclusive) who was diagnosed with a pediatric brain tumor of any histologic subtype, who has now developed recurrent or refractory disease. All patients enrolled in this trial will receive standard of care treatment for recurrent and/or refractory pediatric brain tumors, including systemic agents, prior to receiving the investigational agent. Availability of tissue for sequencing to determine presence of targetable neoantigen. This may be fresh tissue collected as part of routine care, another research project or archived tissue from a previous craniotomy with biopsy, subtotal resection, total gross resection, or re-resection. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Eligibility Criteria for Treatment Administration (Step 2) Step 2 Inclusion Criteria Personalized neoantigen DNA vaccine manufactured for administration. Karnofsky/Lansky performance status ≥ 60% Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Hemoglobin level >8\ 8g/dL Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Any adverse event patients may have experienced during prior therapy must have resolved to ≤ CTCAE v5 grade 1. Any lesions amenable to radiotherapy or palliative radiotherapy (e.g.- bone metastases or metastases causing nerve impingement) should be treated > 4 weeks prior to Step 2 eligibility confirmation and subjects must be fully recovered from the effects of radiation. Systemic corticosteroid therapy is permitted provided dosing is minimal based on age 0.1mg/kg/day with a max of 4mg daily (dexamethasone or equivalent) on the day of vaccine administration. Participants using topical, ocular, intra-articular, or intranasal/inhaled steroids may participate. Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment-related standard premedication are permitted. Bevacizumab will be allowed if given for symptomatic control of vasogenic edema and to avoid high dose of corticosteroids. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Exclusion Criteria: As this is a safety and feasibility study, prior immunotherapy will be permitted. However, any prior immunotherapy must be discontinued at least 2 weeks before vaccine administration. Non-immunologic therapy may be continued. No candidate neoantigen identified during screening. A history of other malignancy ≤ 3 years previous with the exception of non-melanoma skin cancer, any in situ cancer that has been successfully resected and cured, treated superficial bladder cancer, or any early-stage solid tumor that was successfully resected without need for adjuvant radiation or chemotherapy. Receiving any other investigational agents within 4 weeks of beginning study treatment. Known allergy, or history of serious adverse reaction to, vaccines such as anaphylaxis, hives, or respiratory difficulty. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Ongoing or active infection requiring systemic therapy (e.g. active HBV or HCV infection that requires treatment) or causing fever (temperature > 38.1˚C) or subjects with unexplained fever (temperature > 38.1˚C) within 7 days prior to the first vaccine dose. History of immunodeficiency disorder or autoimmune condition requiring active immunosuppressive therapy. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended. Recommend exclusion of specific ART agents based on predicted drug-drug interactions (i.e. for sensitive CYP3A4 substrates, concurrent strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers (efavirenz) should be contraindicated). Administration of live vaccine within 30 days prior to enrollment. Participants may receive the COVID-19 vaccine as long as it is not a live vaccine. Presence of clinically significant increased intracranial pressure (e.g. impending herniation) or hemorrhage, uncontrolled seizures, or requirement for immediate palliative treatment. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of first dose of vaccine. Individuals in whom a measurement of the circumference of the thigh at the midpoint between the hip and knee is < 35 cm. Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue for eligible injection sites (left and right vastus laterals muscles) exceeds 50 mm. Individuals in whom the ability to observe possible local reactions at the eligible injection sites is, in the opinion of the investigator, unacceptably obscured due to a physical condition (e.g. hypertrophic skin patches, keloids, or other conditions which could interfere with the administration procedure or subsequent assessment of local reactogenicity) or permanent body art. Has a metal implant or implantable device within the area of the electroporation injection or has any non-removable electronic stimulation device, such as cardiac demand pacemaker, automatic implantable cardiac defibrillator, nerve stimulator, or deep brain stimulator. Acute or chronic, clinically significant hematologic, pulmonary, cardiovascular, or hepatic or renal functional abnormality as determined by the investigator based on medical history, physical examination, EKG, and/or laboratory screening test. Any chronic or active neurologic disorder, including seizures and epilepsy, excluding a single febrile seizure as a child. Syncopal episode within 12 months of screening.

Ages Eligible for Study
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Maximum Age: 39 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Personalized neoantigen DNA vaccine<br>Patients will receive the vaccine monthly (+/- 3 days) for 6 doses as a priming phase followed by booster injections quarterly (Q3mo) (+/- 7 days) thereafter. Vaccination will continue indefinitely until development of intolerance or disease progression in the case of fatal high grade neoplasms. Otherwise, vaccination will continue until intolerance or one year for non-fatal tumors. Additionally, patients with non-fatal tumors who complete one year of vaccinations and have stable disease will be given the option of resuming vaccinations if they develop subsequent progression. | Biological: Personalized neoantigen DNA vaccine<br>* At each vaccination time point, patients will receive one injection of the neoantigen DNA vaccine, one injection into the vastus lateralis.<br>Device: Ichor TDS-IM v2.0<br>* All study injections will be given intramuscularly using an integrated electroporation device (TDS-IM v2.0 device - Ichor Medical Systems).<br>Procedure: Peripheral blood draw<br>* -After trial enrollment and up to 7 days after the first vaccine dose (baseline); 2 weeks after last dose; time of progression or discontinuation (optional); other time points throughout the study if deemed pertinent to assessment of exploratory objectives (optional)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of adjuvant personalized neoantigen DNA vaccine as measured by the number of grade 3 and 4 adverse events |  | Through 30 days after completion of treatment (estimated to be 13 months) | 
| Feasibility of adjuvant personalized neoantigen DNA vaccine as measured the number of participants that had a neoantigen-specific DNA vaccine generated |  | From time of resection to time of initiation (approximately 12-14 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): At least a 25% increase in the sum of products of perpendicular diameters of at least 1 target lesion, taking as reference the smallest sum of products of perpendicular diameters on study (this includes the baseline sum if that is the smallest on study). The absolute increase in any dimension must be at least 5mm when calculating the products of perpendicular diameters. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy* not caused by comorbid events. | 2 years | 
| Median Overall Survival |  | 2 years |