Clinical Trials /

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

NCT03330197

Description:

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.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Supratentorial Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Ad-RTS-hIL-12 + Veledimex in Pediatric Subjects With Brain Tumors Including DIPG
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: ATI001-103
  • NCT ID: NCT03330197

Conditions

  • Pediatric Brain Tumor
  • Diffuse Intrinsic Pontine Glioma

Interventions

DrugSynonymsArms
Ad-RTS-hIL-12Arm 1 - Closed
Oral Veledimex - Arm 1 (Pediatric Brain Tumor)Arm 1 - Closed
Oral Veledimex - Arm 2 (DIPG)Arm 2 - Open

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1 - ClosedExperimentalIntratumoral Ad-RTS-hIL-12 freehand injection after tumor resection and oral veledimex (activator ligand) in pediatric patients with brain tumors.
  • Ad-RTS-hIL-12
  • Oral Veledimex - Arm 1 (Pediatric Brain Tumor)
Arm 2 - OpenExperimentalIntratumoral Ad-RTS-hIL-12 stereotactic injection and oral veledimex (activator ligand) in pediatric patients with DIPG.
  • Ad-RTS-hIL-12
  • Oral Veledimex - Arm 2 (DIPG)

Eligibility Criteria

        Inclusion Criteria:

          1. 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

          2. 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

          3. 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)

          4. At the time of registration, subjects must have recovered from the toxic effects of
             previous treatments, as determined by the treating physician.

               1. Targeted agents, including small-molecular tyrosine kinase inhibitors: 2 weeks

               2. Other cytotoxic agents: 3 weeks

               3. Nitrosoureas: 6 weeks

               4. Monoclonal antibody immunotherapies (eg, PD-1, CTLA-4): 6 weeks

               5. Vaccine-based and/or viral therapy: 3 months

          5. On a stable or decreasing dose of dexamethasone for the previous 7 days

          6. Able to undergo standard MRI scans with contrast agent before enrollment and after
             treatment

          7. Have age-appropriate functional performance:

               1. Lansky score ≥ 40 or

               2. Karnofsky score > 50 or

               3. Eastern Cooperative Oncology Group (ECOG) score ≤ 2

          8. Have adequate bone marrow reserves and liver and kidney function, as assessed by the
             following laboratory requirements:

               1. Hemoglobin ≥ 8 g/L

               2. Absolute lymphocyte count ≥ 500/mm3

               3. Absolute neutrophil count ≥ 1000/mm3

               4. Platelets ≥ 100,000/mm3 (untransfused [> 5 days] without growth factors)

               5. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age

               6. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for age

               7. Total bilirubin < 1.5 x ULN for age

               8. International normalized ratio (INR) and activated thromboplastin time within
                  normal institutional limits

          9. 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:

          1. Radiotherapy treatment prior to the first veledimex dose:

               1. Focal radiation ≤ 4 weeks

               2. Whole-brain radiation ≤ 6 weeks

               3. 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)

          2. Subjects with clinically significant increased intracranial pressure (eg, impending
             herniation or requirement for immediate palliative treatment) or uncontrolled seizures

          3. Subjects whose body surface area (BSA) would expose them to < 75% or > 125% of the
             target dose

          4. Known immunosuppressive disease, autoimmune condition, and/or chronic viral infection
             (eg, human immunodeficiency virus [HIV], hepatitis)

          5. 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

          6. Use of enzyme-inducing antiepileptic drugs (EIAEDs) within 7 days prior to the first
             dose of study drug

          7. Other concurrent clinically active malignant disease, requiring treatment

          8. Nursing or pregnant females

          9. Prior exposure to veledimex

         10. Use of medications that induce, inhibit, or are substrates of cytochrome p450 (CYP450)
             3A4 within 7 days prior to veledimex

         11. 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.

         12. Presence of any contraindication for a neurosurgical procedure

         13. Unstable or clinically significant concurrent medical condition that would jeopardize
             the safety of a subject and/or their compliance with the protocol
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ziopharm

Trial Keywords

  • DIPG
  • Glioblastoma
  • Anaplastic Astrocytoma
  • High Grade Glioma (HGG) Not Otherwise Specified (NOS)
  • Supratentorial Tumor NOS

Last Updated

July 10, 2020