| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate the safety of either olaptesed pegol in combination with radiation therapy or olaptesed pegol combination with radiation therapy and bevacizumab or pembrolizumab in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status. |
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| E.2.2 | Secondary objectives of the trial |
- To explore the efficacy of olaptesed pegol in combination with radiation therapy on patients with glioblastoma
- To investigate the efficacy of olaptesed pegol in combination with radiation therapy and bevacizumab or pembrolizumab in patients with glioblastoma of unmethylated MGMT promoter status
- To investigate the pharmacokinetics of olaptesed pegol during continuous administration
- To monitor symptoms (NANO) and Quality of Life |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Criteria for inclusion - 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 (e.g., MGMT promotor 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. Status post biopsy or 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)
• 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
Criteria for inclusion - Expansion Group:
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 resection (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 |
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| E.4 | Principal exclusion criteria |
All patients
• 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)
• Prior radiotherapy to the head
• Any other previous or concomitant experimental glioblastoma treatments
• Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
• 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, 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
• Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
Dose Escalation Cohorts
• 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)
Arms A and B
• Planned hypofractionated radiotherapy
• 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
• Patients with a history of arterial or venous thrombosis (or any other disease) requiring permanent intake of anticoagulants (Arm A only)
• Prolongation of coagulation factors ≥ 2.5 x ULN (Arm A only)
Arm C
• 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
• 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
• Evidence of acute intracranial / intra-tumoral hemorrhage
• 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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Progression Free Survival (PFS) at 6 months (PFS-6)
• Median progression-free survival (mPFS)
• Median overall survival (mOS)
• Tumor vascularisation as per vascular MRI scans at baseline and following 2, 4, and 6 months
• Topography of recurrence
• Determination of maximum tolerated dose (MTD)
• Definition of recommended Phase 2 dose (RP2D)
• Olaptesed pegol plasma levels at steady state
• Neurologic Assessment in Neuro-Oncology (NANO) assessment
• Quality of Life |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| single arm, dose escalation, combination therapy with irradiation /Bevacizumab / Pembrolizumab |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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