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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Olaptesed pegol
* Radiation: Radiotherapy
* Drug: Bevacizumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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: 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 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 (>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 (>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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 dose escalation and a 3-arm expansion group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: 200 mg Olaptesed pegol + Radiotherapy<br>olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6 | Drug: Olaptesed pegol<br>* Olaptesed pegol continuous administration for 26 weeks<br>* Other names: NOX-A12;Radiation: Radiotherapy<br>* Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions<br>|
| Experimental: Cohort 2: 400 mg Olaptesed pegol + Radiotherapy<br>olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6 | Drug: Olaptesed pegol<br>* Olaptesed pegol continuous administration for 26 weeks<br>* Other names: NOX-A12;Radiation: Radiotherapy<br>* Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions<br>|
| Experimental: Cohort 3: 600 mg Olaptesed pegol + Radiotherapy<br>olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6 | Drug: Olaptesed pegol<br>* Olaptesed pegol continuous administration for 26 weeks<br>* Other names: NOX-A12;Radiation: Radiotherapy<br>* Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions<br>|
| Experimental: Expansion group, Arm A: 600 mg Olaptesed pegol + Radiotherapy + 10 mg/kg Bevacizumab<br>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<br>* Olaptesed pegol continuous administration for 26 weeks<br>* Other names: NOX-A12;Radiation: Radiotherapy<br>* Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions<br>Drug: Bevacizumab<br>* Bevacizumab every 2 weeks i.v. for 26 weeks<br>* Other names: MVASI;|
| Experimental: Expansion group, Arm B: 600 mg Olaptesed pegol + Radiotherapy<br>olaptesed pegol weekly for 26 weeks administered i.v. by continuous infusion plus radiotherapy during weeks 1-6, completely resected patients | Drug: Olaptesed pegol<br>* Olaptesed pegol continuous administration for 26 weeks<br>* Other names: NOX-A12;Radiation: Radiotherapy<br>* Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions<br>|
| Experimental: Expansion group, Arm C: 600 mg Olaptesed pegol + Radiotherapy + 200 mg Pembrolizumab<br>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<br>* Olaptesed pegol continuous administration for 26 weeks<br>* Other names: NOX-A12;Radiation: Radiotherapy<br>* Radiotherapy in weeks 1-6; cumulative dose of 60 Gy in 2 Gy fractions<br>Drug: Pembrolizumab<br>* Pembrolizumab every 3 weeks i.v. for 26 weeks<br>* Other names: KEYTRUDA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Number of patients with treatment-related adverse events as assessed by CTCAE | Number of patients with treatment-related adverse events as assessed by CTCAE | 26 weeks | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MGMT promoter, Brain tumor, Radiotherapy, Brain cancer, Tumor microenvironment, Bevacizumab, Pembrolizumab, Glioblastoma, NOX-A12, Olaptesed pegol, Spiegelmer, Stromal cell-derived factor-1 (SDF-1), CXCL12, Radiation