ADI-PEG 20 Plus Radiotherapy and Temozolomide in Subjects With Glioblastoma Multiforme (GBM)

Phase 1-2 Trial of ADI-PEG 20 Plus Radiotherapy and Temozolomide in Subjects With Newly Diagnosed Glioblastoma Multiforme (GBM)

A randomized, double-blind, placebo-controlled study. Weekly ADI-PEG 20 (36 mg/m2) or placebo will be combined with Stupp Protocol (Stupp 2005) radiotherapy and TMZ

Study Overview

• Status: Active, not recruiting
• Conditions: Glioblastoma Multiforme (GBM)
• Intervention / Treatment: Drug: ADI-PEG 20; Drug: Temozolomide; Drug: Placebo

Detailed Description

A randomized, double-blind, placebo-controlled study. Weekly ADI-PEG 20 (36 mg/m2) or placebo will be combined with Stupp Protocol (Stupp 2005) radiotherapy and TMZ as noted for the Phase 1 portion. Furthermore, ADI-PEG 20 or placebo treatment may continue after adjuvant TMZ if there is no progressive disease, for up to a total of 2 years of ADI-PEG 20 or placebo treatment. In addition, after 24 weeks (6 cycles) subjects may also continue adjuvant TMZ along with ADI-PEG 20 or placebo, in the absence of disease progression, as noted above, if clinically indicated in the investigator's judgement. MRI is to be performed post-surgery(biopsy), and then at 1, 3 and 6 months after completion of radiotherapy and then every 3 months for up to 24 months.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Korea
  • Jeollanam-do
    • Hwasun-gun, Jeollanam-do, South Korea, 58128
      • Chonnam National University Hwasun Hospital
  • Jongno-gu
    • Seoul, Jongno-gu, South Korea, 03080
      • Seoul National University Hospital
  • Seocho-gu
    • Seoul, Seocho-gu, South Korea, 06591
      • Seoul St. Mary's Hospital, The Catholic University of Korea
  • Seodaemun-gu
    • Seoul, Seodaemun-gu, South Korea, 03722
      • Severance Hospital Yonsei University
  • Seongnam
    • Gyeonggi-do, Seongnam, South Korea, 13620
      • Seoul National University Bundang Hospital
• Taiwan
  • Anle Dist
    • Keelung, Anle Dist, Taiwan, 204201
      • Chang Gung-Medical Foundation-Keelung (CGMF-KL)
  • Guishan Dist
    • Taoyuan District, Guishan Dist, Taiwan, 333423
      • Chang Gung Memorial Hospital, Linkou Branch
  • Niaosong Dist
    • Kaohsiung City, Niaosong Dist, Taiwan, 833401
      • Chang Gung Medical Foundation-Kaohsiung
  • Tamsui Dist
    • New Taipei City, Tamsui Dist, Taiwan, 251404
      • Mackay Memorial Hospital-Tamsui Branch
  • Zhongzheng Dist
    • Taipei, Zhongzheng Dist, Taiwan, 100229
      • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Newly diagnosed, histologically confirmed glioblastoma, IDH-wildtype and the WHO Grade 4 of astrocytoma, IDH-mutant by WHO 2021 classification of brain tumors, non-resectable or partially resected or resected.
2. Age 20 - 75 years.
3. Karnofsky Performance Status (KPS) ≥ 60.
4. Expected life expectancy ≥16 weeks.
5. Stable or decreasing corticosteroids (5 mg/day dexamethasone or equivalent) within 5 days before the first dose of ADI-PEG 20.
6. No prior systemic therapy, immunotherapy, investigational agent, or radiation therapy.
7. Recovered from any prior surgery and no major surgery within 2 weeks of initiating treatment (other than GBM surgery). Surgery for placement of vascular access devices is acceptable.
8. Female subjects and male subjects must be asked to use appropriate contraception for both the male and female for the duration of the study and for at least 30 days after the last administration of ADI-PEG 20 or placebo and at least 6 months after the last administration of TMZ. Male partners of female subjects and female partners of male subjects must agree to use two forms of contraception or agree to refrain from intercourse for the duration of the study if they are of childbearing potential. Females of childbearing potential must not be pregnant at the start of the study, and a serum human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into the study. If positive HCG pregnancy test, further evaluation to rule out pregnancy must be performed according to GCP before this subject is deemed eligible. Females not of childbearing potential must be post-menopausal (defined as cessation of regular menstrual period for at least 12 months).
9. Informed consent must be obtained prior to study initiation.
10. No concurrent investigational studies are allowed.
11. Absolute neutrophil count (ANC) ≥ 1500/μL.
12. Platelets ≥ 100,000/μL.
13. Serum uric acid ≤ 8 mg/dL (with or without medication control).
14. Creatinine clearance must be ≥ 40 mL/min/1.73 m2 (calculated using the Cockcroft-Gault equation: calculated creatinine clearance = (140-age (yrs)) × body weight (kg) (×0.85 if female) / 72 × serum creatinine (mg/dl).
15. Total bilirubin ≤ 2 x upper limit of normal.
16. ALT and AST ≤ 3 x upper limit of normal, unless liver metastases present then ≤ 5 x upper limit normal.

Exclusion Criteria:

1. Serious infection requiring treatment with systemically administered antibiotics at the time of study entrance, or an infection requiring systemic antibiotic therapy within 7 days prior to the first dose of study treatment.
2. Pregnancy or lactation.
3. Expected non-compliance.
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), cardiac arrhythmia, or psychiatric illness, social situations that would limit compliance with study requirements.
5. Subjects with history of another primary cancer, including co-existent second malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present or in the opinion of the investigator will not affect patient outcome.
6. Subjects who had been treated with ADI-PEG 20 previously.
7. History of uncontrolled seizure disorder not related to underlying cancer.
8. Known HIV positivity, or active hepatitis B infection, or active hepatitis C infection (testing not required).
9. Allergy to pegylated compounds.
10. Allergy to E. coli drug products (such as GMCSF).
11. Allergy to TMZ or any of its components.
12. History of hypersensitivity to dacarbazine.
13. Placement of Gliadel wafer at surgery.
14. Having a co-existing condition requiring systemic treatment with either corticosteroids or immunosuppressive medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ADI-PEG 20 plus Radiotherapy and Temozolomide; ADI-PEG 20 Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) Radiotherapy Dose: 60 Gy in 30 daily (Monday-Friday) fractions of 2 Gy each; to start within 4 weeks of surgery (diagnostic and/or resection) Temozolomide Dose: 75 mg/m2 daily during radiotherapy; 150-200 mg/m2 for 5 days every 4 weeks (1 cycle) x 6 cycles during maintenance period Route of Administration: oral or intravenous	Drug: ADI-PEG 20; Investigational Medicine; Drug: Temozolomide; Radiotherapy and TMZ are standard front-line therapy for newly diagnosed GBM.
Placebo Comparator: Placebo plus Radiotherapy and Temozolomide; Placebo Dose: 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) Radiotherapy Dose: 60 Gy in 30 daily (Monday-Friday) fractions of 2 Gy each; to start within 4 weeks of surgery (diagnostic and/or resection) Temozolomide Dose: 75 mg/m2 daily during radiotherapy; 150-200 mg/m2 for 5 days every 4 weeks (1 cycle) x 6 cycles during maintenance period Route of Administration: oral or intravenous	Drug: Temozolomide; Radiotherapy and TMZ are standard front-line therapy for newly diagnosed GBM.; Drug: Placebo; Investigational Medicine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	In the ADI-PEG 20 treated arm compared to the placebo arm, and determine if predefined patient subtypes or associated biomarkers uniquely benefit from the treatment	Through study completion, 2.5 year anticipated

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS will be reported as the time subject experience from the start of treatment to disease progression or death, measured in month.	Through study completion, 2.5 year anticipated
Duration of response (DOR)	DOR is reported as the time from when the tumor begins to respond to treatment (first occurrence of CR or PR) until disease progression or deterioration occurs (diagnosis of disease progression), measured in month.	Through study completion, 2.5 year anticipated
Tumor response rate	Response rate is usually measured in percentage (%). It represents the proportion of subjects whose tumors achieve partial or complete response among those who received treatment.	Through study completion, 2.5 year anticipated
Pharmacokinetics of ADI-PEG 20	ADI-PEG 20 Plasma Concentrations are measured over time, samples are collected before the dosing, and on week 0, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28 and 32, then every 4 weeks until week 52 or End of treatment visit.	Up to week 52 or End of treatment visit
Pharmacodynamics of ADI-PEG 20	Citrulline and Arginine plasma concentrations are measured over time, samples are collected before the dosing, and on week 0, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28 and 32, then every 4 weeks until week 52 or End of treatment visit.	Up to week 52 or End of treatment visit
Immunogenicity of ADI-PEG 20	Antibodies for ADI-PEG 20, Anti-PEG antibodies are measured in plasma over time, samples are collected before the dosing, and on week 0, 1, 2, 4, 6, 8, 10, 12, 13, 16, 20, 24, then once a month for three months, followed by once every three months until week 52 or End of treatment visit.	Up to week 52 or End of treatment visit
Safety and tolerability of ADI-PEG 20	Safety and tolerability in the ADI-PEG 20 treated arm compared to the placebo arm. Incidence of Treatment-Emergent Adverse Events from first dose to time of progression or death. The severity of all AEs will be assessed according to the NCI CTCAE Scale version 5.	Through study completion, 2.5 year anticipated

Collaborators and Investigators

• Sponsor: Polaris Group
• Investigators: Principal Investigator: Kuo-Chen Wei, M.D., Chang Gung Memorial Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2020
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): May 30, 2027

Study Registration Dates

• First Submitted: September 4, 2020
• First Submitted That Met QC Criteria: October 8, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Estimated): August 26, 2025
• Last Update Submitted That Met QC Criteria: August 19, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: arginine; argininosuccinate synthetase; arginine deiminase
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Substandard Drugs; Pharmaceutical Preparations; Azoles; Dacarbazine; Triazenes; Imidazoles; Temozolomide; Counterfeit Drugs; ADI PEG20
• Other Study ID Numbers: POLARIS2020-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No