A Phase 1/2 interventional study of ADI-PEG 20 (Arginine deiminase pegylated) and Temozolomide (TMZ) in Glioblastoma, High-Grade Glioma (WHO III-IV) and High-grade Glioma, sponsored by Sabine Mueller, MD, PhD. Not yet recruiting at 1 site in United States. Open to participants aged 3 Years to 39 Years. Per ClinicalTrials.gov, last updated 2026-09-15.
Sponsored by Sabine Mueller, MD, PhD · Phase 1/2, Interventional, and Treatment
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).
PRIMARY OBJECTIVES:
I. To evaluate the safety and estimate the RP2D of ADI-PEG 20 in combination with RT and TMZ in with children, adolescents, and young adults with newly diagnosed high-grade glioma, and the RP2D of ADI-PEG 20 during maintenance therapy with TMZ (Phase 1)
II. To assess the anti-tumor activity of the combination of ADI-PEG 20 with RT and TMZ based on progression-free survival (PFS) at 12 months for HGG histone-WT participants, 12 months for H3K27 altered DMG, and 10 months for H3G34 mutant DHG in children, adolescents, and young adult participants (Phase 2)
EXPLORATORY OBJECTIVES:
I. To assess the anti-tumor activity of the combination of ADI-PEG 20 with RT and TMZ based on overall survival at 12 months for HGG histone-WT, Histone 3 lysine 27 (H3K27) altered DMG, and Histone 3 G34-mutant (H3G34) DHGs. II. To correlate argininosuccinate synthase 1 (ASS1) and arginase tumor expression and Cerebral spinal fluid (CSF)/systemic arginine levels with survival.
III. To correlate levels of cell free DNA and other liquid biomarkers in the context of imaging response criteria and clinical outcome.
IV. To assess the microbiome in the context of imaging response criteria and clinical outcome.
V. To describe the pharmacokinetics of ADI-PEG 20 in combination with radiotherapy and TMZ and in maintenance treatment in children, adolescent and young adults with HGG.
VI. To describe the pharmacodynamics of ADI-PEG 20 in combination with radiotherapy and TMZ and in maintenance treatment in children, adolescent and young adults with HGG.
VII. To assess immunogenicity of ADI-PEG 20 in combination with radiotherapy and TMZ and in maintenance treatment in children, adolescent and young adults with HGG.
VIII. To explore the use of serial single voxel magnetic resonance (MR) spectroscopy to evaluate on-target tumor metabolic changes with the use of ADI-PEG 20.
IX. To explore sex differences in arginine metabolism in participants with newly diagnosed high-grade glioma pre and post treatment with ADI-PEG 20.
X. To characterize immune micro-environment of tumor edge in comparison to tumor core. Inclusion of normal/reactive brain tissue will be used to compare baseline reactive transcriptional signature, including immune pathways activated in peritumoral regions of the brain.
OUTLINE: Participants will be enrolled into Phase 1 (dose escalation) where the pediatric RP2D of ADI-PEG 20 in combination with radiotherapy and daily TMZ (DLT period 1) as well as ADI-PEG 20 with TMZ during maintenance (DLT period 2) will be determined through a rolling-6 design and then followed by a planned Phase 2. Participants in Phase 2 will further be analyzed by cohort based on confirmed diagnosis of the following expressed biomarkers:
Cohort 1: Participants with newly diagnosed histone wild type (WT) HGG. (N=25).
Cohort 2: Participants with newly diagnosed H3K27 altered diffuse midline gliomas (DMG). (N=30).
Cohort 3: Participants with newly diagnosed H3G34 mutant diffuse hemispheric gliomas (DHG). (N=18).
Participants can receive treatment up to 104 weeks. After completing the 30-day toxicity evaluation period, participants will enter follow-up and additional follow-up data will be documented under the Pediatric Neuro-oncology Consortium (PNOC) COMP protocol. Participants will be followed under the PNOC COMP protocol until death or withdrawal from the study.
Participants must have histologically and molecularly confirmed newly diagnosed World Health Organization (WHO) grade 3 or 4 glioma.
Phase 2:
Age:
Phase 1:
o 3 to \<18 years of age.
Phase 2:
Organ Function Requirements:
Exclusion Criteria:
Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.
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)
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)
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)
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)
Given intramuscularly (IM)
Also known as: ADI-PEG 20
Given orally (PO)
Also known as: TMZ
Undergo RT
Also known as: RT
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 10 months
Plan to share: Yes — De-identified datasets will be shared with study collaborators during the course of the study.
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Sabine Mueller, MD, PhD