Glioblastoma Treatment With Irradiation and Olaptesed Pegol (NOX-A12) in MGMT Unmethylated Patients (GLORIA)

Single-arm Dose-escalation Phase 1/2 Study of Olaptesed Pegol (NOX-A12) in Combination With Irradiation in Inoperable or Partially Resected First-line Glioblastoma Patients With Unmethylated MGMT Promoter With a 3-arm Expansion Group Including Fully Resected Patients and Combination With Bevacizumab or Pembrolizumab

The purpose of this study is to obtain first, exploratory information on the safety and efficacy of (i) olaptesed pegol in combination with radiation therapy in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status either not amenable to resection (biopsy only) or after incomplete tumor resection, (ii) olaptesed pegol in combination with radiation therapy and bevacizumab in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status either not amenable to resection (biopsy only) or after incomplete or complete tumor resection, (iii) olaptesed pegol in combination with radiation therapy in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status after complete tumor resection, and (iv) olaptesed pegol in combination with radiation therapy and pembrolizumab in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status after either complete or incomplete tumor resection.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Olaptesed pegol; Radiation: Radiotherapy; Drug: Bevacizumab; Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany
    • Klinik und Poliklinik für Neurologie Schwerpunkt Klinische Neuroonkologie
  • Essen, Germany
    • Klinik für Neurologie
  • Leipzig, Germany
    • Klinik für Strahlentherapie und Radioonkologie
  • Mannheim, Germany
    • Klinik für Strahlentherapie und Radioonkologie
  • Münster, Germany
    • Klinik für Neurologie mit Institut für Translationale Neurologie
  • Tübingen, Germany
    • Abteilung Neurologie mit interdisziplinärem Schwerpunkt Neuroonkologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria Dose Escalation Cohorts:

1. Written informed consent
2. Age ≥18 years
3. Patient agreement to diagnostic and scientific work-up of glioblastoma tissue obtained during the preceding surgery or biopsy
4. Patient agrees to subcutaneous port implantation
5. Newly diagnosed, histologically confirmed, supratentorial WHO grade IV glioblastoma
6. Status post biopsy or incomplete resection
7. Unmethylated MGMT promoter status
8. Maximum Eastern Cooperative Oncology Group (ECOG) score 2
9. Estimated minimum life expectancy 3 months
10. Stable or decreasing dose of corticosteroids during the week prior to inclusion

11. The following laboratory parameters should be within the ranges specified:

    • Total bilirubin ≤ 1.5 x upper limit normal (ULN)
    • Creatinine ≤ 1.5 x ULN or glomerular filtration rate ≥ 60 mL/min/1.73m²
    • ALT (alanine transaminase) ≤ 3 x ULN
    • AST (aspartate transaminase) ≤ 3 x ULN
12. Female patients of child-bearing potential must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly such as contraceptive implants, vaginal rings, sterilization, or sexual abstinence)" during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations)
13. Male patients must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP

Inclusion Criteria Expansion Group:

1. Written informed consent
2. Age ≥ 18 years
3. Patient agreement to diagnostic and scientific work-up of glioblastoma tissue obtained during the preceding surgery or biopsy (e.g., MGMT promoter analysis, cytogenetic markers such as IDH-1 mutations, etc.)
4. Patient agrees to subcutaneous port implantation
5. Newly diagnosed, histologically confirmed, supratentorial WHO grade IV glioblastoma
6. a) Status post biopsy or incomplete (detectable residual tumor as per postoperative T1-weighted, contrast-enhanced MRI scan) or complete resection (Arm A) OR b) Status post complete resection (Arm B) OR c) Status post complete or incomplete resection (circumscribed enhancing tumor ≤ 5.0 cm in largest diameter as per postoperative T1-weighted, contrast-enhanced MRI scan) (Arm C)
7. Unmethylated MGMT promoter status
8. Maximum Eastern Cooperative Oncology Group (ECOG) score 2
9. Estimated minimum life expectancy 3 months
10. Stable or decreasing dose of corticosteroids during the week prior to inclusion

11. The following laboratory parameters should be within the ranges specified:

    • Total bilirubin ≤ 1.5 x upper limit normal (ULN)
    • Creatinine ≤ 1.5 x ULN or glomerular filtration rate ≥ 60 mL/min/1.73m²
    • ALT (alanine transaminase) ≤ 3 x ULN
    • AST (aspartate transaminase) ≤ 3 x ULN
12. Female patients of child-bearing potential must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly such as contraceptive implants, vaginal rings, sterilization, or sexual abstinence) during and for 3 months (6 months Arm A, 4 months Arm C) following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations)
13. Male patients must use an effective barrier method of contraception during study and for 3 months (6 months Arm A, 4 months Arm C) following the last dose if sexually active with a FCBP

Exclusion Criteria Dose Escalation Cohorts:

1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents, olaptesed pegol or polyethylene glycol
4. Cytostatic therapy (chemotherapy) within the past 5 years
5. History of other cancers (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for ≥ 5 years)
6. Clinically significant or uncontrolled cardiovascular disease
7. Prior radiotherapy to the head
8. Any other previous or concomitant experimental glioblastoma treatments
9. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
10. Pregnancy or lactation
11. Uncontrolled intercurrent illness; patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations
12. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
13. Prior enrolment into this study

Exclusion Criteria Expansion Group Arms A and B:

1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents, bevacizumab (Arm A only) olaptesed pegol or polyethylene glycol
4. Planned hypofractionated radiotherapy
5. Cytostatic therapy (chemotherapy) within the past 5 years
6. History of other cancers (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for ≥ 5 years)
7. Secondary malignancy which is currently active

8. Clinically significant or uncontrolled cardiovascular disease, including

   • Myocardial infarction in the previous 12 months
   • Uncontrolled angina
   • Congestive heart failure (New York Heart Association functional classification of ≥2)
   • Diagnosed or suspected congenital long QT syndrome
   • QTc prolongation on an electrocardiogram prior to entry (>470 ms)
   • Uncontrolled hypertension (blood pressure ≥ 160/95 mmHg)
   • Heart rate <50/min on the baseline electrocardiogram
   • History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
   • Cerebrovascular accident
9. Prior radiotherapy to the head
10. Any other previous or concomitant experimental glioblastoma treatments
11. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
12. Patients with a history of arterial or venous thrombosis (or any other disease) requiring permanent intake of anticoagulants (Arm A only)
13. Pregnancy or lactation
14. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), diabetes mellitus, or subjects with either of the following: fasting blood glucose (FBG defined as fasting for at least 8 hours) ≥ 200 mg/dL (7.0 mmol/L), or HbA1c ≥ 8%, chronic renal disease, pancreatitis, chronic pulmonary disease, auto-immune diseases, or psychiatric illness/social situations that would limit compliance with study requirements. Patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations
15. Prolongation of coagulation factors ≥ 2.5 x ULN (Arm A only)
16. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
17. Prior enrolment into this study

Exclusion Criteria Expansion Group Arms C:

1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents olaptesed pegol or polyethylene glycol or pembrolizumab (≥ Grade 3)
4. Biopsy-only of GBM with less than 20% of tumor removed
5. Presence of extracranial metastatic or leptomeningeal disease
6. Severe hypersensitivity (≥ Grade 3) to other monoclonal antibodies
7. Receiving immunosuppressive therapy
8. Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agent
9. Planned hypofractionated radiotherapy
10. Cytostatic therapy (chemotherapy) within the past 5 years
11. History of other cancers or secondary malignancy which is currently active (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for ≥ 5 years)

12. Clinically significant or uncontrolled cardiovascular disease, including

    • Myocardial infarction in the previous 12 months
    • Uncontrolled angina
    • Congestive heart failure (New York Heart Association functional classification of ≥2)
    • Diagnosed or suspected congenital long QT syndrome
    • QTc prolongation on an electrocardiogram prior to entry (>470 ms)
    • Uncontrolled hypertension (blood pressure ≥ 160/95 mmHg)
    • Heart rate <50/min on the baseline electrocardiogram
    • History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
    • Cerebrovascular accident
13. Prior radiotherapy to the head
14. Evidence of acute intracranial / intra-tumoral hemorrhage
15. Any other previous or concomitant experimental glioblastoma treatments
16. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
17. Pregnancy or lactation
18. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), diabetes mellitus, or subjects with either of the following: fasting blood glucose (FBG defined as fasting for at least 8 hours) ≥ 200 mg/dL (7.0 mmol/L), or HbA1c ≥ 8%, chronic renal disease, pancreatitis, chronic pulmonary disease, auto-immune diseases or psychiatric illness/social situations that would limit compliance with study requirements. Patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations.
19. Received a live vaccine within 30 days prior to the first dose of study drug.
20. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Previously treated brain metastases may participate provided these remain stable
21. Known history of HIV infection, hepatitis B or hepatitis C infection
22. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
23. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or current pneumonitis / interstitial lung disease
24. Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (exceeding 10 mg daily of prednisone) or any other form of immunosuppressive therapy
25. High dose of corticosteroids (> 4mg/day of dexamethasone or equivalent for at least 3 consecutive days) within two weeks prior to the first dose of study drug
26. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
27. Prior enrolment into this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: 200 mg Olaptesed pegol + Radiotherapy; olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6	Drug: Olaptesed pegol; Olaptesed pegol continuous administration for 26 weeks; Other Names: NOX-A12; Radiation: Radiotherapy; Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions
Experimental: Cohort 2: 400 mg Olaptesed pegol + Radiotherapy; olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6	Drug: Olaptesed pegol; Olaptesed pegol continuous administration for 26 weeks; Other Names: NOX-A12; Radiation: Radiotherapy; Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions
Experimental: Cohort 3: 600 mg Olaptesed pegol + Radiotherapy; olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6	Drug: Olaptesed pegol; Olaptesed pegol continuous administration for 26 weeks; Other Names: NOX-A12; Radiation: Radiotherapy; Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions
Experimental: Expansion group, Arm A: 600 mg Olaptesed pegol + Radiotherapy + 10 mg/kg Bevacizumab; olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion, bevacizumab every two weeks for 26 weeks plus radiotherapy during weeks 1-6, incompletely or not resected patients	Drug: Olaptesed pegol; Olaptesed pegol continuous administration for 26 weeks; Other Names: NOX-A12; Radiation: Radiotherapy; Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions; Drug: Bevacizumab; Bevacizumab every 2 weeks i.v. for 26 weeks; Other Names: MVASI
Experimental: Expansion group, Arm B: 600 mg Olaptesed pegol + Radiotherapy; olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6, completely resected patients	Drug: Olaptesed pegol; Olaptesed pegol continuous administration for 26 weeks; Other Names: NOX-A12; Radiation: Radiotherapy; Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions
Experimental: Expansion group, Arm C: 600 mg Olaptesed pegol + Radiotherapy + 200 mg Pembrolizumab; olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion, pembrolizumab every three weeks for 26 weeks plus radiotherapy during weeks 1-6, incompletely resected patients	Drug: Olaptesed pegol; Olaptesed pegol continuous administration for 26 weeks; Other Names: NOX-A12; Radiation: Radiotherapy; Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions; Drug: Pembrolizumab; Pembrolizumab every 3 weeks i.v. for 26 weeks; Other Names: KEYTRUDA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - Number of patients with treatment-related adverse events as assessed by CTCAE	Number of patients with treatment-related adverse events as assessed by CTCAE	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy - progression free survival at 6 months (PFS-6)	Progression free survival at 6 months (PFS-6) in %	6 months
Efficacy - Median progression-free survival (mPFS)	Median progression-free survival (mPFS) in months	24 months
Efficacy - Median overall survival (mOS)	Median overall survival (mOS) in months	24 months
Efficacy - Tumor vascularization as per vascular MRI	Changes from baseline in tumor vascularization over time as %cerebral blood volume	24 months
Plasma level of olaptesed pegol	concentration of olaptesed pegol in plasma in µmol/L	26 weeks
Quality of Life (QoL) EORTC QLQ-C30 Module	Quality of Life measures are recorded according to EORTC QLQ30 module, which is validated for cancer patients in general and measured as a unit of scale. This is a standard tool for assessing patient reported quality of Life along time during treatment.	24 months
Quality of Life (QoL) EORTC QLQ BN-20 Module	Quality of Life measures are recorded according to EORTC QLQ BN-20 module, which is validated for brain tumor patients and measured as a unit of scale. This is a standard tool for assessing patient reported quality of Life along time during treatment.	24 months
Neurologic functions as measured by the NANO scale	Change from baseline in neurologic performance scores by Neurologic Assessment in Neuro-Oncology (NANO) scale as an objective and quantifiable metric of neurologic function evaluable during a routine office examination. The NANO Scale evaluates 9 major domains of neurologic function, with each domain being scored on a range from 0 to 2 or 3.	24 months

Collaborators and Investigators

• Sponsor: TME Pharma AG

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2019
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 25, 2019
• First Submitted That Met QC Criteria: October 8, 2019
• First Posted (Actual): October 10, 2019

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Bevacizumab; Radiotherapy; Pembrolizumab; Brain tumor; Glioblastoma; NOX-A12; Olaptesed pegol; Spiegelmer; Stromal cell-derived factor-1 (SDF-1); CXCL12; Tumor microenvironment; Radiation; Brain cancer; MGMT promoter
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immune Checkpoint Inhibitors; Bevacizumab; Pembrolizumab
• Other Study ID Numbers: SNOXA12C401; 2018-004064-62 (EudraCT Number)

Drug and device information, study documents

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