Oncolytic Virus Ad-TD-nsIL12 for Progressive Pediatric Diffuse Intrinsic Pontine Glioma

This is a single-arm, single-center, drug safety assessment clinical trial with a 3+3 dose escalation design, to observe the safety, tolerability and toxicity of a novel oncolytic virus Ad-TD-nsIL12 intratumoral injection in progressive DIPG patients (NCI-CTCAE V5.0).

Study Overview

• Status: Recruiting
• Conditions: Diffuse Intrinsic Pontine Glioma; Adverse Drug Event; Oncolytic Virus
• Intervention / Treatment: Biological: Ad-TD-nsIL12

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Xiao Qian, Dr.; Phone Number: 18020295435; Email: ryan521q@sina.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100010
      • Recruiting
      • Sanbo Brain Hospital, Capital Medical University
      • Contact: Weihai Ning, Dr.; Phone Number: +86 15961868172; Email: sanboocean@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Informed consent of the parents or patient.
2. After surgical resection, biopsy, chemotherapy, or radiation therapy, tumor progression must be confirmed by MRI scan.
3. Biopsy is performed prior to injection of Ad-TD-nsIL12 to confirm DIPG (frozen section-based).
4. Pre-enrollment patients LPS (patients aged ≥1 and <16 years) and KPS (patients aged ≥16 years) ≥ 50.
5. Patient must be, in the investigator opinion, able to comply with all the protocol procedures.
6. Age 1-18 years.
7. A negative pregnancy test in fertile women (women are considered of childbearing potential (WOCBP) after menarche, unless permanently infertile, including hysterectomy, bilateral salpingectomy, and bilateral oophorectomy).
8. Lesion considered by the investigator to be accessible for stereotactic biopsy.

Exclusion Criteria:

1. Serious infections or intercurrent conditions, including but not limited to severe renal failure, liver failure, heart failure, or bone marrow failure, which are not permitted for inclusion according to the investigator's criteria. Patients must be afebrile (<38℃) at the time of viral therapy.
2. Other investigational medications within 30 days prior to viral treatment.
3. Participants with immunodeficiency, autoimmune disease, or active hepatitis.
4. Any medical or psychological condition that might interfere with the patient's ability to participate if older than 16 years or parents ability when younger than 16, or give informed consent or would compromise the patient's ability to tolerate therapy or any disease that will obscure toxicity or dangerously alter drug metabolism.
5. Tumor with multiple location.
6. Pregnant or breast-feeding females.
7. Severe bone marrow hypoplasia.
8. Transaminases (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)) or total bilirubin > 3 times the upper limit of normal.
9. Neutrophils < 1x10^9/L.
10. Platelets ≤ 100x10^9/L.
11. Hemoglobin < 9g/dl.
12. Patients with Li-Fraumini syndrome or a known germline defect in the retinoblastoma gene or its associated pathways.
13. Administer any type of vaccine within 30 days prior to Ad-TD-nsIL12 administration.
14. Blood transfusions or drugs (such as G-CSF) within 28 days before viral treatment to treat pancytopenia or other hematological disorders.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental Group; Multiple intratumoral injections of Ad-TD-nsIL12.

Biological: Ad-TD-nsIL12; After stereotactic biopsy, the Ommaya reservoir will be inserted through the biopsy channel and two injections of Ad-TD-nsIL12 will be delivered after surgery by Ommaya reservoir (with an interval of 3days). The interval between following injections in the subsequent treatment period will be 3 weeks ±4 days. The assigned dose for each patient will be 3x10^9vp, 1x10^10vp or 3x10^10 vp suspended in 1 ml NS according to cohort design.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of Ad-TD-nsIL12 intratumoral injection in progressive pediatric DIPG patients.	The trial will look for possible hematologic and neurologic toxicity of Ad-TD-nsIL12 by NCI-CTCAE v5.0 to determine maximum tolerated dose of this oncolytic adenovirus.	3 months after virus injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QoL	To measure quality of life baseline assessment and any changes over time by PedsQLTM criteria.	2 years after virus injection
Sample Collection	Pre- and post- treatment tumor tissue will be collected and tested to determine the immune response of patients. Collected blood will be used to test possible hematotoxicity of Ad-TD-nsIL12.	3 months after virus injection
Tumor response	To determine tumor response by RAPNO criteria	3 months after virus injection
Over-all survival	To determine overall survival at 12 months (OS12).	12 months after virus injection

Collaborators and Investigators

• Sponsor: Capital Medical University
• Investigators: Principal Investigator: Hongwei Zhang, Prof., Capital Medical University

Publications and helpful links

General Publications

• Zhang Z, Zhang C, Miao J, Wang Z, Wang Z, Cheng Z, Wang P, Dunmall LSC, Lemoine NR, Wang Y. A Tumor-Targeted Replicating Oncolytic Adenovirus Ad-TD-nsIL12 as a Promising Therapeutic Agent for Human Esophageal Squamous Cell Carcinoma. Cells. 2020 Nov 10;9(11):2438. doi: 10.3390/cells9112438.
• Bortolanza S, Bunuales M, Otano I, Gonzalez-Aseguinolaza G, Ortiz-de-Solorzano C, Perez D, Prieto J, Hernandez-Alcoceba R. Treatment of pancreatic cancer with an oncolytic adenovirus expressing interleukin-12 in Syrian hamsters. Mol Ther. 2009 Apr;17(4):614-22. doi: 10.1038/mt.2009.9. Epub 2009 Feb 17.
• Wang P, Li X, Wang J, Gao D, Li Y, Li H, Chu Y, Zhang Z, Liu H, Jiang G, Cheng Z, Wang S, Dong J, Feng B, Chard LS, Lemoine NR, Wang Y. Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Nat Commun. 2017 Nov 9;8(1):1395. doi: 10.1038/s41467-017-01385-8. Erratum In: Nat Commun. 2018 Jan 10;9(1):203.

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2023
• Primary Completion (Estimated): January 4, 2025
• Study Completion (Estimated): January 4, 2028

Study Registration Dates

• First Submitted: December 18, 2022
• First Submitted That Met QC Criteria: January 29, 2023
• First Posted (Actual): February 8, 2023

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 25, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Glioma; Drug-Related Side Effects and Adverse Reactions; Diffuse Intrinsic Pontine Glioma
• Other Study ID Numbers: Ad-TD-nsIL12 for Pro-DIPG

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No