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About
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, and (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.
Further arms are included (i) to establish safety for the combination of olaptesed pegol at three different doses in addition to radiotherapy and bevacizumab, (ii) to explore the benefit of combining olaptesed pegol at different dose levels with bevacizumab in order to define the doses to move forward into a subsequent randomized dose-finding study, (iii) to explore the contribution of the therapy components olaptesed pegol and bevacizumab to patient benefit and (iv) to put the clinical outcome of these treatment regimens into perspective with the standard of care treatment with temozolomide and radiotherapy.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
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:
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:
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:
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:
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
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
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
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
Primary purpose
Allocation
Interventional model
Masking
117 participants in 11 patient groups
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Central trial contact
Diana Beyer, Dr.
Data sourced from clinicaltrials.gov
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