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

Inclusion criteria

Dose Escalation Cohorts:

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

• Written informed consent
• Age ≥ 18 years
• 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.)
• Patient agrees to subcutaneous port implantation
• Newly diagnosed, histologically confirmed, supratentorial WHO grade IV glioblastoma
• 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)
• Unmethylated MGMT promoter status
• Maximum Eastern Cooperative Oncology Group (ECOG) score 2
• Estimated minimum life expectancy 3 months
• Stable or decreasing dose of corticosteroids during the week prior to inclusion
• 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
• 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)
• 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

Inclusion criteria

Expansion Group Arms D, E, F, G, and H:

• Written informed consent
• Age ≥ 18 years
• Patient agreement to diagnostic and scientific work-up of glioblastoma tissue obtained during the preceding surgery (e.g., MGMT promoter analysis, cytogenetic markers such as IDH-1 mutations, etc.)
• Patient agrees to subcutaneous port implantation
• Newly diagnosed, histologically confirmed, supratentorial WHO grade 4 glioblastoma, IDH-wildtype according to the 2021 World Health Organization Criteria for CNS tumors
• Status post incomplete resection (detectable residual tumor as per postoperative T1-weighted, contrast-enhanced MRI scan)
• Unmethylated MGMT promoter status
• Maximum Eastern Cooperative Oncology Group (ECOG) score 2
• Estimated minimum life expectancy 3 months
• Stable or decreasing dose of corticosteroids during the week prior to inclusion
• The following laboratory parameters should be within the ranges specified:

• Total bilirubin ≤ 1.5 x upper limit normal (ULN)
• Body surface area (BSA) adjusted glomerular filtration rate (GFR) ≥ 60 mL/min (BSA-adjusted eGFR CKD-EPI (mL/min) = [eGFR CKD-EPI (mL/min/1.73 m²) x BSA (m²)]/ 1.73; BSA calculated by Du Bois formula)
• Alanine transaminase (ALT) ≤ 3 x ULN
• Aspartate transaminase (AST) ≤ 3 x ULN
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L and platelet count ≥ 100 x 10^9/L
• Female patients of child-bearing potential (FCBP) 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 6 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations)
• Male patients must use an effective barrier method of contraception during study and for 6 months following the last dose if sexually active with a FCBP

Exclusion criteria

Dose Escalation Cohorts:

• Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
• 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
• Contra-indication or known hypersensitivity to MRI contrast agents, olaptesed pegol or polyethylene glycol
• Cytostatic therapy (chemotherapy) within the past 5 years
• 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)
• Clinically significant or uncontrolled cardiovascular disease
• Prior radiotherapy to the head
• Any other previous or concomitant experimental glioblastoma treatments
• Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
• Pregnancy or lactation
• 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
• Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
• Prior enrolment into this study

Exclusion criteria

Expansion Group Arms A and B:

• Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
• 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
• Contra-indication or known hypersensitivity to MRI contrast agents, bevacizumab (Arm A only) olaptesed pegol or polyethylene glycol
• Planned hypofractionated radiotherapy
• Cytostatic therapy (chemotherapy) within the past 5 years
• 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)
• Secondary malignancy which is currently active
• 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 (QTc(Bazett) >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
• Prior radiotherapy to the head
• Any other previous or concomitant experimental glioblastoma treatments
• Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
• Patients with a history of arterial or venous thrombosis (or any other disease) requiring permanent intake of anticoagulants (Arm A only)
• Pregnancy or lactation
• 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
• Prolongation of coagulation factors ≥ 2.5 x ULN (Arm A only)
• Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
• Prior enrolment into this study

Exclusion criteria

Expansion Group Arms C:

• Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
• 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
• Contra-indication or known hypersensitivity to MRI contrast agents olaptesed pegol or polyethylene glycol or pembrolizumab (≥ Grade 3)
• Biopsy-only of GBM with less than 20% of tumor removed
• Presence of extracranial metastatic or leptomeningeal disease
• Severe hypersensitivity (≥ Grade 3) to other monoclonal antibodies
• Receiving immunosuppressive therapy
• Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agent
• Planned hypofractionated radiotherapy
• Cytostatic therapy (chemotherapy) within the past 5 years
• 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)
• 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 (QTc(Bazett) >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
• Prior radiotherapy to the head
• Evidence of acute intracranial / intra-tumoral hemorrhage
• Any other previous or concomitant experimental glioblastoma treatments
• Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
• Pregnancy or lactation
• 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.
• Received a live vaccine within 30 days prior to the first dose of study drug.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Previously treated brain metastases may participate provided these remain stable
• Known history of HIV infection, hepatitis B or hepatitis C infection
• Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
• History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or current pneumonitis / interstitial lung disease
• Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (exceeding 10 mg daily of prednisone) or any other form of immunosuppressive therapy
• 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
• Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
• Prior enrolment into this study

Exclusion criteria

Expansion Group Arms D, E, F, G and H:

• Patients with tumors harboring IDH mutations
• Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
• Participation in any clinical research study with administration of an investigational drug or therapy within 30 days prior to screening visit or observation period of competing studies
• Contra-indication or known hypersensitivity to MRI contrast agents, bevacizumab, olaptesed pegol or polyethylene glycol
• Planned hypofractionated radiotherapy
• Chemotherapy (cytotoxic/cytostatic) within the past 5 years
• 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)
• Secondary malignancy which is currently active
• 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 the electrocardiogram prior to inclusion (QTc(Bazett) >470 ms)
• Uncontrolled hypertension (blood pressure ≥ 160/95 mmHg)
• Heart rate <50/min on the electrocardiogram prior to inclusion
• History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
• Cerebrovascular accident
• Prior radiotherapy to the head
• Any other previous or concomitant experimental glioblastoma treatments
• Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
• Patients with a history of arterial or venous thrombosis (or any other disease) requiring permanent intake of anticoagulants
• Pregnancy or lactation
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), diabetes mellitus, or patients 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.
• Prolongation of coagulation factors ≥ 2.5 x ULN
• Treatment not initiated within 6 weeks after surgery of glioblastoma
• Prior enrolment into this study
• History of hypersensitivity to dacarbazine (DTIC)
• History of hypersensitivity reaction (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to temozolomide or any of its components
• Severe myelosuppression (ANC <1.5 x 10^9/L and platelet count <100 x 10^9/L)
• Major surgery within 28 days prior to treatment start
• Non-healing wounds