| Eligibility |
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:
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
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
Exclusion Criteria Expansion Group Arms A and B:
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, bevacizumab (Arm A
only) olaptesed pegol or polyethylene glycol
4. Planned hypofractionated radiotherapy
5. Cytostatic therapy (chemotherapy) within the past 5 years
6. 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)
7. Secondary malignancy which is currently active
8. 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
9. Prior radiotherapy to the head
10. Any other previous or concomitant experimental glioblastoma treatments
11. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
12. Patients with a history of arterial or venous thrombosis (or any other disease)
requiring permanent intake of anticoagulants (Arm A only)
13. Pregnancy or lactation
14. 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
15. Prolongation of coagulation factors = 2.5 x ULN (Arm A only)
16. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
17. Prior enrolment into this study
Exclusion Criteria Expansion Group Arms C:
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 or pembrolizumab (= Grade 3)
4. Biopsy-only of GBM with less than 20% of tumor removed
5. Presence of extracranial metastatic or leptomeningeal disease
6. Severe hypersensitivity (= Grade 3) to other monoclonal antibodies
7. Receiving immunosuppressive therapy
8. Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2
agent
9. Planned hypofractionated radiotherapy
10. Cytostatic therapy (chemotherapy) within the past 5 years
11. 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)
12. 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
13. Prior radiotherapy to the head
14. Evidence of acute intracranial / intra-tumoral hemorrhage
15. Any other previous or concomitant experimental glioblastoma treatments
16. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
17. Pregnancy or lactation
18. 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.
19. Received a live vaccine within 30 days prior to the first dose of study drug.
20. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Previously treated brain metastases may participate provided these remain stable
21. Known history of HIV infection, hepatitis B or hepatitis C infection
22. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.
with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
23. History of (non-infectious) pneumonitis / interstitial lung disease that required
steroids or current pneumonitis / interstitial lung disease
24. Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (exceeding 10
mg daily of prednisone) or any other form of immunosuppressive therapy
25. 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
26. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
27. Prior enrolment into this study
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