Glioblastoma
Conditions
Keywords
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
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, 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.
Interventions
DRUGOlaptesed pegol
Olaptesed pegol continuous i.v. administration
RADIATIONRadiotherapy
Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions
DRUGBevacizumab
Bevacizumab every 2 weeks i.v. infusion
DRUGPembrolizumab
Pembrolizumab every 3 weeks i.v. for 26 weeks
DRUGTemozolomide (TMZ)
oral treatment according to current SPC
Sponsors
TME Pharma AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 dose escalation (sequential) followed by a multiple-arm expansion group (parallel)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 Arms A, B and C: 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 Inclusion Criteria Expansion Group Arms D, E, F, G, and H: 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 (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 4 glioblastoma, IDH-wildtype according to the 2021 World Health Organization Criteria for CNS tumors 6. Status post incomplete resection (detectable residual tumor as per postoperative T1-weighted, contrast-enhanced MRI scan) 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) * 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 12. 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) 13. 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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Number of patients with treatment-related adverse events as assessed by CTCAE | through study completion, an average of 3 years | Number of patients with treatment-related adverse events as assessed by CTCAE |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Median progression-free survival (mPFS) | until end of treatment, an average 1 year | Median progression-free survival (mPFS) in months |
| Efficacy - Median overall survival (mOS) | through study completion, an average of 3 years | Median overall survival (mOS) in months |
| Efficacy - Landmark overall survival at 18 months (OS18) | 18 months | — |
| Overall response rate (ORR) | through study completion, an average of 3 years | — |
| Efficacy - progression free survival at 6 months (PFS-6) | 6 months | Progression free survival at 6 months (PFS-6) in % |
| Quality of Life (QoL) EORTC QLQ-C30 Module | through study completion, an average of 3 years | 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. |
| Quality of Life (QoL) EORTC QLQ BN-20 Module | through study completion, an average of 3 years | 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. |
| Efficacy - Tumor vascularization as per vascular MRI | through study completion, an average of 3 years | Changes from baseline in tumor vascularization over time as %cerebral blood volume |
| Neurologic functions as measured by the NANO scale | 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. |
| Plasma level of olaptesed pegol | 9 weeks after treatment start | concentration of olaptesed pegol in plasma in µmol/L |
Countries
Germany
Outcome results
None listed