A Study of Ad-RTS-hIL-12 + Veledimex in Pediatric Subjects With Brain Tumors Including DIPG

Study Overview
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Brief Summary
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This research study involves an investigational product: Ad-RTS-hIL-12 given with veledimex for production of human IL-12. IL-12 is a protein that can improve the body's natural response to disease by enhancing the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. The main purpose of this study is to evaluate the safety and tolerability of a single tumor injection of Ad-RTS-hIL-12 given with oral veledimex in the pediatric population.

Detailed Description
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Eligible patients will be stratified to one of two arms, according to clinical indication for tumor resection. Pediatric patients who are scheduled for craniotomy and tumor resection will receive one dose of veledimex before the resection procedure. Ad-RTS-hIL-12 will be administered by free-hand injection. Patients will continue on oral veledimex for 14 days. This arm has been completed and is currently closed to enrollment. Pediatric patients with diffuse intrinsic pontine glioma (DIPG) will receive Ad-RTS-hIL-12 by stereotactic injection and then will continue on oral veledimex for 14 days. The study is divided into three periods: the screening period, the treatment period and the follow-up period.

Official Title
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A Phase I/II Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the Presence of the Activator Ligand Veledimex in Pediatric Brain Tumor Subjects

Conditions
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Pediatric Brain Tumor, Diffuse Intrinsic Pontine Glioma

Intervention / Treatment
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* Biological: Ad-RTS-hIL-12
* Drug: Oral Veledimex - Arm 1 (Pediatric Brain Tumor)
* Drug: Oral Veledimex - Arm 2 (DIPG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects ≤ 21 years-of-age with the demonstrated ability to swallow capsules whole and who are willing to provide access to previously obtained biopsy results Provision of written informed consent and assent, when applicable, for tumor resection, stereotactic surgery, tumor biopsy, sample collection, and/or treatment with study drug prior to undergoing any study-specific procedures Arm 1: Evidence of recurrent or progressive supratentorial tumor, which has shown a > 25% increase in bi dimensional measurements by MRI or is refractory with significant neuro deterioration that is not otherwise explained with no known curative therapy, not in direct continuity with the ventricular system (e.g., there is physical separation between the tumor and ventricle, the tumor does not open directly into the ventricular system). Arm 2: Clinical presentation of DIPG and compatible MRI with approximately 2/3 of the pons included and without evidence of dissemination. Subjects should be ≥ 2 weeks and ≤ 10 weeks post standard focal radiotherapy (ie, dose of 5400 to 5960 cGy and maximum dexamethasone of 1 mg/m2/day) At the time of registration, subjects must have recovered from the toxic effects of previous treatments, as determined by the treating physician. Targeted agents, including small-molecular tyrosine kinase inhibitors: 2 weeks Other cytotoxic agents: 3 weeks Nitrosoureas: 6 weeks Monoclonal antibody immunotherapies (eg, PD-1, CTLA-4): 6 weeks Vaccine-based and/or viral therapy: 3 months On a stable or decreasing dose of dexamethasone for the previous 7 days Able to undergo standard MRI scans with contrast agent before enrollment and after treatment Have age-appropriate functional performance: Lansky score ≥ 40 or Karnofsky score > 50 or Eastern Cooperative Oncology Group (ECOG) score ≤ 2 Have adequate bone marrow reserves and liver and kidney function, as assessed by the following laboratory requirements: Hemoglobin ≥ 8 g/L Absolute lymphocyte count ≥ 500/mm3 Absolute neutrophil count ≥ 1000/mm3 Platelets ≥ 100,000/mm3 (untransfused [> 5 days] without growth factors) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for age Total bilirubin < 1.5 x ULN for age International normalized ratio (INR) and activated thromboplastin time within normal institutional limits Male and female subjects of childbearing potential must agree to use a highly reliable method of birth control (expected failure rate < 1% per year) from the Screening visit through 28 days after the last dose of study drug. Women of childbearing potential must have a negative pregnancy test at screening. Exclusion Criteria: Radiotherapy treatment prior to the first veledimex dose: Focal radiation ≤ 4 weeks Whole-brain radiation ≤ 6 weeks Cranio-spinal radiation ≤ 12 weeks NOTE: Subjects in Arm 2 (ie, with DIPG) must be ≥ 2 weeks and ≤ 10 weeks after standard focal radiotherapy (dose of 5400 to 5960 cGy and maximum dexamethasone of 1 mg/m2/day) Subjects with clinically significant increased intracranial pressure (eg, impending herniation or requirement for immediate palliative treatment) or uncontrolled seizures Subjects whose body surface area (BSA) would expose them to < 75% or > 125% of the target dose Known immunosuppressive disease, autoimmune condition, and/or chronic viral infection (eg, human immunodeficiency virus [HIV], hepatitis) Use of systemic antibacterial, antifungal, or antiviral medications for the treatment of acute clinically significant infection within 2 weeks of first veledimex dose. Concomitant therapy for chronic infections is not allowed. Subjects must be afebrile prior to Ad-RTS-hIL-12 injection; only prophylactic antibiotic use is allowed perioperatively Use of enzyme-inducing antiepileptic drugs (EIAEDs) within 7 days prior to the first dose of study drug Other concurrent clinically active malignant disease, requiring treatment Nursing or pregnant females Prior exposure to veledimex Use of medications that induce, inhibit, or are substrates of cytochrome p450 (CYP450) 3A4 within 7 days prior to veledimex Use of heparin or acetylsalicylic acid (ASA). The use of systemic heparinization, or any ASA containing medications, is prohibited during active dosing with veledimex. Prophylactic heparin SC, per institutional protocol, or heparin when used for maintaining patency of an access port of a PICC line is permitted. Presence of any contraindication for a neurosurgical procedure Unstable or clinically significant concurrent medical condition that would jeopardize the safety of a subject and/or their compliance with the protocol

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 21 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - Closed<br>Intratumoral Ad-RTS-hIL-12 freehand injection after tumor resection and oral veledimex (activator ligand) in pediatric patients with brain tumors. | Biological: Ad-RTS-hIL-12<br>* 2.0 x 10^11 viral particles (vp) per injection, one intratumoral injection of Ad-RTS-hIL-12<br>Drug: Oral Veledimex - Arm 1 (Pediatric Brain Tumor)<br>* 1 dose level (10mg/day) 15 oral daily doses of veledimex<br>|
| Experimental: Arm 2 - Open<br>Intratumoral Ad-RTS-hIL-12 stereotactic injection and oral veledimex (activator ligand) in pediatric patients with DIPG. | Biological: Ad-RTS-hIL-12<br>* 2.0 x 10^11 viral particles (vp) per injection, one intratumoral injection of Ad-RTS-hIL-12<br>Drug: Oral Veledimex - Arm 2 (DIPG)<br>* 2 dose levels (10mg/day, 20mg/day) 14 oral daily doses of veledimex<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety and tolerability of intratumoral Ad-RTS-hIL-12 and veledimex as measured by dose limiting toxicities and compliance. |  | From Day 0 through Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To measure the veledimex in blood and brain tumor by using the LC-MS method |  | From Day 0 through 30 days after the last dose of veledimex | 
| Evaluate preliminary efficacy of Ad-RTS-hIL-12 and veledimex by assessing survival and tumor response rates |  | 2 Years | 
| Measure immune response of Ad-RTS-hIL-12 and veledimex by a quantitative multiplex immunoassay for determination of IL-12 and IFNg levels |  | 28 Days | 
| Subjects with Ad-RTS-hIL-12 and veledimex related adverse events will be assessed for safety by CTCAE v5.0 |  | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DIPG, Glioblastoma, Anaplastic Astrocytoma, High Grade Glioma (HGG) Not Otherwise Specified (NOS), Supratentorial Tumor NOS