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 Multiple-arm Expansion Group
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.
• 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
• 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
• 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