Combination ADI-PEG 20, TMZ, and RT for Treatment of Newly Diagnosed High-grade Glioma (HGG)

NCT07389278 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 250814NCI-2026-00045
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label, intra-patient dose escalation, to evaluate ADI-PEG 20, in combination with Temozolomide (TMZ) and radiation therapy (RT) in children, adolescents and young adult patients with newly diagnosed high grade glioma (HGG).

Conditions

High-Grade Glioma (WHO III-IV); High-grade Glioma; Glioblastoma; Diffuse Midline Glioma, H3 K27M-Mutant; Diffuse Hemispheric Glioma, H3G34 Mutant

Outcome Measures

Primary Outcomes (4)

• Proportion of participants with Treatment-emergent Adverse Events (TrAE) (Phase 1)

  Proportion of participants in Phase 1 with treatment-emergent adverse events as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) will be reported.

  Up to 104 weeks

• Progression-Free Survival (PFS) for HGG histone-WT (Phase 2, Cohort 1)

  PFS for participants in Phase 2, Cohort 1 is defined as the median number of days participants remained progression free at 12 months. Participants without a documented tumor progression or death will be censored on the date of their last evaluable tumor assessment. Participants without a documented tumor progression or death before initiation of another anti-tumor therapy will be censored on the date of their last evaluable tumor assessment prior to or on the date of the new anti-tumor therapy. PFS estimates will be obtained from the Kaplan-Meier curve. An appropriate variance term that accounts for censoring Greenwood's formula) will be used to construct the 95% confidence intervals.

  Up to 12 months

• Progression-Free Survival (PFS) for H3K27 altered diffuse midline glioma (DMG) (Phase 2, Cohort 2)

  PFS for participants in Phase 2, Cohort 2 is defined as the median number of days participants remained progression free at 12 months. Participants without a documented tumor progression or death will be censored on the date of their last evaluable tumor assessment. Participants without a documented tumor progression or death before initiation of another anti-tumor therapy will be censored on the date of their last evaluable tumor assessment prior to or on the date of the new anti-tumor therapy. PFS estimates will be obtained from the Kaplan-Meier curve. An appropriate variance term that accounts for censoring Greenwood's formula) will be used to construct the 95% confidence intervals.

  Up to 12 months

• Progression-Free Survival (PFS) for H3G34 mutant diffuse hemispheric glioma (DHG) (Phase 2, Cohort 3)

  PFS for participants in Phase 2, Cohort 3 is defined as the median number of days participants remained progression free at 10 months. Participants without a documented tumor progression or death will be censored on the date of their last evaluable tumor assessment. Participants without a documented tumor progression or death before initiation of another anti-tumor therapy will be censored on the date of their last evaluable tumor assessment prior to or on the date of the new anti-tumor therapy. PFS estimates will be obtained from the Kaplan-Meier curve. An appropriate variance term that accounts for censoring Greenwood's formula) will be used to construct the 95% confidence intervals.

  Up to 10 months

Study Arms (4)

Phase 1 (Starting Dose: ADI-PEG 20 36mg/m^2)

EXPERIMENTAL

Participants will receive injection of 36 mg/m\^2 of ADI-PEG 20 once weekly in the concomitant phase and maintenance phases given prior to the start of RT. Participants will also receive daily oral (PO) temozolomide (TMZ) with dosage based on age and dosing phase (concomitant, then maintenance) starting on the same day as Radiotherapy (RT). RT will be given in standard fractions (total dose 59.4 Gy) over 6 weeks. The boost volume, when present, will receive an additional 5.4 Gy for a total of 59.4 Gy. Post-RT, Participants will continue to receive weekly ADI-PEG 20 as monotherapy and then proceed to first cycle of maintenance therapy 28 days (+7 days) after completion of RT, in the absence of dose-limiting toxicities (DLT) or progressive disease. The maintenance phase consists of ten cycles (28 days long) of combination chemotherapy with ADI-PEG 20 and TMZ. Participants will receive no more than 104 weeks of ADI-PEG 20 therapy

Drug: Temozolomide (TMZ); Radiation: Standard of Care Radiation Therapy (RT)

Phase 2 (Cohort 1) - Histone Wild Type (WT) HGG

EXPERIMENTAL

Participants with WT HGG will be treated at the recommended phase 2 dose (RP2D) of ADI-PEG 20 determined in Phase 1 in combination with TMZ. Participants who complete the combined treatment and maintenance phase may continue receiving monotherapy treatment as extended maintenance for up to 10 additional cycles, provided there is no unacceptable toxicity, disease progression, or withdrawal of consent. ADI-PEG 20 treatment may continue for up to 104 weeks.

Drug: ADI-PEG 20 (Arginine deiminase pegylated); Drug: Temozolomide (TMZ); Radiation: Standard of Care Radiation Therapy (RT)

Phase 2 (Cohort 2) - H3K27 Altered Diffuse Midline Gliomas (DMG)

EXPERIMENTAL

Participants will be treated at the recommended phase 2 dose (RP2D) of ADI-PEG 20 determined in Phase 1. Participants who complete the combined treatment and maintenance phase may continue receiving monotherapy treatment as extended maintenance for up to 10 additional cycles, provided there is no unacceptable toxicity, disease progression, or withdrawal of consent. ADI-PEG 20 treatment may continue for up to 104 weeks. After completing the 30-day toxicity evaluation period, participants will enter follow-up. Follow-up procedures will be documented under the PNOC COMP protocol, except for protocol-defined follow-up procedures. Participants will be followed under the PNOC COMP protocol until death or withdrawal from the study.

Drug: ADI-PEG 20 (Arginine deiminase pegylated); Drug: Temozolomide (TMZ); Radiation: Standard of Care Radiation Therapy (RT)

Phase 2 (Cohort 3) - H3G34 Mutant Diffuse Hemispheric Gliomas (DHG)

EXPERIMENTAL

Participants will be treated at the recommended phase 2 dose (RP2D) of ADI-PEG 20 determined in Phase 1. Participants who complete the combined treatment and maintenance phase may continue receiving monotherapy treatment as extended maintenance for up to 10 additional cycles, provided there is no unacceptable toxicity, disease progression, or withdrawal of consent. ADI-PEG 20 treatment may continue for up to 104 weeks. After completing the 30-day toxicity evaluation period, participants will enter follow-up. Follow-up procedures will be documented under the PNOC COMP protocol, except for protocol-defined follow-up procedures. Participants will be followed under the PNOC COMP protocol until death or withdrawal from the study.

Drug: ADI-PEG 20 (Arginine deiminase pegylated); Drug: Temozolomide (TMZ); Radiation: Standard of Care Radiation Therapy (RT)

Interventions

Temozolomide (TMZ) DRUG

Given orally (PO)

Also known as: TMZ

Phase 1 (Starting Dose: ADI-PEG 20 36mg/m^2); Phase 2 (Cohort 1) - Histone Wild Type (WT) HGG; Phase 2 (Cohort 2) - H3K27 Altered Diffuse Midline Gliomas (DMG); Phase 2 (Cohort 3) - H3G34 Mutant Diffuse Hemispheric Gliomas (DHG)

Standard of Care Radiation Therapy (RT) RADIATION

Undergo RT

Also known as: RT

Phase 1 (Starting Dose: ADI-PEG 20 36mg/m^2); Phase 2 (Cohort 1) - Histone Wild Type (WT) HGG; Phase 2 (Cohort 2) - H3K27 Altered Diffuse Midline Gliomas (DMG); Phase 2 (Cohort 3) - H3G34 Mutant Diffuse Hemispheric Gliomas (DHG)

ADI-PEG 20 (Arginine deiminase pegylated) DRUG

Given intramuscularly (IM)

Also known as: ADI-PEG 20

Phase 2 (Cohort 1) - Histone Wild Type (WT) HGG; Phase 2 (Cohort 2) - H3K27 Altered Diffuse Midline Gliomas (DMG); Phase 2 (Cohort 3) - H3G34 Mutant Diffuse Hemispheric Gliomas (DHG)

Eligibility Criteria

• Age: 3 Years - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participants must have histologically and molecularly confirmed newly diagnosed World Health Organization (WHO) grade 3 or 4 glioma.
• Phase 1: any newly diagnosed HGG (including DMG of any location and primary spinal cord tumors).
• Phase 2:
• Cohort 1: Newly diagnosed non-pontine, non-spinal cord HGG histone-wildtype.
• Cohort 2: Newly diagnosed non-pontine, non-spinal cord H3K27 altered diffuse midline glioma (DMG).
• Cohort 3: Newly diagnosed non-pontine, non-spinal cord H3G34 mutant diffuse hemispheric glioma (DHG).
• Prior surgery: must have undergone maximal safe resection. For patients with DMG of the pons, biopsy is sufficient.
• Prior Therapy: Participants must NOT have received ANY prior therapy (except surgery) before enrollment on study.
• Tumor Tissue Requirement: Participants must have sufficient tumor tissue (5-10 unstained formalin-fixed paraffin-embedded (FFPE) slides or a tumor block) for study enrollment.
• Age:
• Phase 1:
• o 3 to \<18 years of age.
• Phase 2:
• Cohort 1: 3 to 25 years of age.
• Cohorts 2 \& 3: 3 to 39 years of age.

You may not qualify if:

• Participants who have received any systemic therapy or RT, including any investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ADI-PEG 20 such as pegylated compounds.
• Phase 2 cohorts: tumors with epicenter in pons or spinal cord
• Participants with metastatic or leptomeningeal disease. Multi-focal disease should be discussed with the study chairs,
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection that would interfere with the study.
• Women of childbearing potential must not be pregnant or breast-feeding.
• Human immunodeficiency virus (HIV)-positive participants will be ineligible if HIV therapy regimen has not been stable for at least 4 weeks or there is intent to change the regimen within 8 weeks following enrollment, or if they are severely immunocompromised.
• Corrected QT Interval (QTc) cutoff \>480 ms.
• Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.

Sponsors & Collaborators

• Sabine Mueller, MD, PhD: lead

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Glioblastoma; Glioma

Interventions

ADI PEG20; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Sabine Mueller, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Tom Davidson, MD

  Children's Hospital Los Angeles

  STUDY CHAIR

Central Study Contacts

PNOC Operations Office

CONTACT

415-502-1600; PNOC034@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 28, 2026
• First Posted: February 5, 2026
• Study Start: March 9, 2026
• Primary Completion (Estimated): June 30, 2032
• Study Completion (Estimated): June 30, 2035
• Last Updated: February 5, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (1)