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

• ClinicalTrials.gov Identifier: NCT04121455
• Recruitment Status: Active, not recruiting
• First Posted: October 10, 2019
• Last Update Posted: June 22, 2023
• Sponsor: TME Pharma AG
• Information provided by (Responsible Party): TME Pharma AG

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Glioblastoma	Drug: Olaptesed pegol; Radiation: Radiotherapy; Drug: Bevacizumab; Drug: Pembrolizumab	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: 3+3 dose escalation and a 3-arm expansion group
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: September 12, 2019
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: KEYTRUDA

Outcome Measures

Primary Outcome Measures :

1. Safety - Number of patients with treatment-related adverse events as assessed by CTCAE [ Time Frame: 26 weeks ]
   Number of patients with treatment-related adverse events as assessed by CTCAE

Secondary Outcome Measures :

1. Efficacy - progression free survival at 6 months (PFS-6) [ Time Frame: 6 months ]
   Progression free survival at 6 months (PFS-6) in %
2. Efficacy - Median progression-free survival (mPFS) [ Time Frame: 24 months ]
   Median progression-free survival (mPFS) in months
3. Efficacy - Median overall survival (mOS) [ Time Frame: 24 months ]
   Median overall survival (mOS) in months
4. Efficacy - Tumor vascularization as per vascular MRI [ Time Frame: 24 months ]
   Changes from baseline in tumor vascularization over time as %cerebral blood volume
5. Plasma level of olaptesed pegol [ Time Frame: 26 weeks ]
   concentration of olaptesed pegol in plasma in µmol/L
6. Quality of Life (QoL) EORTC QLQ-C30 Module [ Time Frame: 24 months ]
   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.
7. Quality of Life (QoL) EORTC QLQ BN-20 Module [ Time Frame: 24 months ]
   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.
8. Neurologic functions as measured by the NANO scale [ Time Frame: 24 months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Germany

Klinik und Poliklinik für Neurologie Schwerpunkt Klinische Neuroonkologie

Bonn, Germany

Klinik für Neurologie

Essen, Germany

Klinik für Strahlentherapie und Radioonkologie

Leipzig, Germany

Klinik für Strahlentherapie und Radioonkologie

Mannheim, Germany

Klinik für Neurologie mit Institut für Translationale Neurologie

Münster, Germany

Abteilung Neurologie mit interdisziplinärem Schwerpunkt Neuroonkologie

Tübingen, Germany

Sponsors and Collaborators

TME Pharma AG

More Information

• Responsible Party: TME Pharma AG
• ClinicalTrials.gov Identifier: NCT04121455
• Other Study ID Numbers: SNOXA12C401; 2018-004064-62 ( EudraCT Number )
• First Posted: October 10, 2019
• Last Update Posted: June 22, 2023
• Last Verified: June 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by TME Pharma AG:

Glioblastoma; NOX-A12; Olaptesed pegol; Spiegelmer; Stromal cell-derived factor-1 (SDF-1); CXCL12; Radiation; MGMT promoter; Brain tumor; Radiotherapy; Brain cancer; Tumor microenvironment; Bevacizumab; Pembrolizumab

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Bevacizumab; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action