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

Primary Purpose

Pediatric Brain Tumor, Diffuse Intrinsic Pontine Glioma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ad-RTS-hIL-12
Oral Veledimex - Arm 1 (Pediatric Brain Tumor)
Oral Veledimex - Arm 2 (DIPG)
Sponsored by
Alaunos Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pediatric Brain Tumor focused on measuring DIPG, Glioblastoma, Anaplastic Astrocytoma, High Grade Glioma (HGG) Not Otherwise Specified (NOS), Supratentorial Tumor NOS

Eligibility Criteria

0 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California San Francisco, Benioff Children's Hospital
  • Lurie Children's Hospital of Chicago
  • Dana- Farber Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm 1 - Closed

Arm 2 - Open

Arm Description

Intratumoral Ad-RTS-hIL-12 freehand injection after tumor resection and oral veledimex (activator ligand) in pediatric patients with brain tumors.

Intratumoral Ad-RTS-hIL-12 stereotactic injection and oral veledimex (activator ligand) in pediatric patients with DIPG.

Outcomes

Primary Outcome Measures

The safety and tolerability of intratumoral Ad-RTS-hIL-12 and veledimex as measured by dose limiting toxicities and compliance.

Secondary Outcome Measures

To measure the veledimex in blood and brain tumor by using the LC-MS method
Evaluate preliminary efficacy of Ad-RTS-hIL-12 and veledimex by assessing survival and tumor response rates
Measure immune response of Ad-RTS-hIL-12 and veledimex by a quantitative multiplex immunoassay for determination of IL-12 and IFNg levels
Subjects with Ad-RTS-hIL-12 and veledimex related adverse events will be assessed for safety by CTCAE v5.0

Full Information

First Posted
October 16, 2017
Last Updated
November 3, 2021
Sponsor
Alaunos Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT03330197
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Terminated
Why Stopped
Sponsor decision due to slow accrual
Study Start Date
September 26, 2017 (Actual)
Primary Completion Date
September 10, 2021 (Actual)
Study Completion Date
September 10, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alaunos Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pediatric Brain Tumor, Diffuse Intrinsic Pontine Glioma
Keywords
DIPG, Glioblastoma, Anaplastic Astrocytoma, High Grade Glioma (HGG) Not Otherwise Specified (NOS), Supratentorial Tumor NOS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm 1 - Closed
Arm Type
Experimental
Arm Description
Intratumoral Ad-RTS-hIL-12 freehand injection after tumor resection and oral veledimex (activator ligand) in pediatric patients with brain tumors.
Arm Title
Arm 2 - Open
Arm Type
Experimental
Arm Description
Intratumoral Ad-RTS-hIL-12 stereotactic injection and oral veledimex (activator ligand) in pediatric patients with DIPG.
Intervention Type
Biological
Intervention Name(s)
Ad-RTS-hIL-12
Intervention Description
2.0 x 10^11 viral particles (vp) per injection, one intratumoral injection of Ad-RTS-hIL-12
Intervention Type
Drug
Intervention Name(s)
Oral Veledimex - Arm 1 (Pediatric Brain Tumor)
Intervention Description
1 dose level (10mg/day) 15 oral daily doses of veledimex
Intervention Type
Drug
Intervention Name(s)
Oral Veledimex - Arm 2 (DIPG)
Intervention Description
2 dose levels (10mg/day, 20mg/day) 14 oral daily doses of veledimex
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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
Title
Evaluate preliminary efficacy of Ad-RTS-hIL-12 and veledimex by assessing survival and tumor response rates
Time Frame
2 Years
Title
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
Title
Subjects with Ad-RTS-hIL-12 and veledimex related adverse events will be assessed for safety by CTCAE v5.0
Time Frame
2 Years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
0 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jill Buck
Organizational Affiliation
ZIOPHARM Oncology, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
University of California San Francisco, Benioff Children's Hospital
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Facility Name
Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Dana- Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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