Glioblastoma treatment with irradiation and olaptesed pegol (NOX-A12) in unmethylated patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

TME Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Sep 2019 → ongoing

Decision date (initial)

2024-04-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-510964-21-00

EudraCT number

2018-004064-62

WHO UTN

U1111-1301-3759

ClinicalTrials.gov

NCT04121455

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Safety

Dose Escalation Cohorts und Expansion Group Arms A-C:
• 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


Expansion Group Arms D-H:
• To investigate the safety of either olaptesed pegol combination with radiation therapy or olaptesed pegol combination with radiation therapy and bevacizumab in patients with newly diagnosed glioblastoma of unmethylated MGMT promoter status

Secondary objectives 12

1. Dose Escalation Cohorts und Expansion Group Arms A-C:
2. • To explore the efficacy of olaptesed pegol in combination with radiation therapy on patients with glioblastoma
3. • 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
4. • To investigate the pharmacokinetics of olaptesed pegol during continuous administration
5. • To monitor symptoms (NANO) and QoL
6. Expansion Group Arms D-H:
7. • To explore the efficacy of olaptesed pegol in combination with radiation therapy
8. • To investigate the efficacy of olaptesed pegol at different dose levels in combination with radiation therapy and bevacizumab
9. • To investigate the contribution of components olaptesed pegol and bevacizumab to patient benefit
10. • To define olaptesed pegol doses to move forward into a subsequent randomized dose finding study
11. • To investigate the olaptesed pegol plasma levels during continuous administration
12. • To investigate QoL

Conditions and MedDRA coding

Glioblastoma

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 42

1. Dose Escalation Cohorts:
2. 4. Patient agrees to subcutaneous port implantation
3. 5. Newly diagnosed, histologically confirmed, supratentorial WHO grade IV glioblastoma
4. 6. Status post biopsy or incomplete resection (detectable residual tumor as per postoperative T1-weighted, contrast-enhanced MRI scan)
5. 7. Unmethylated MGMT promoter status
6. 8. Maximum Eastern Cooperative Oncology Group (ECOG) score 2
7. Expansion Group Arms A-C:
8. 1. Written informed consent
9. 2. Age ≥ 18 years
10. 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.)
11. 4. Patient agrees to subcutaneous port implantation
12. 9. Estimated minimum life expectancy 3 months
13. 5. Newly diagnosed, histologically confirmed, supratentorial WHO grade IV glioblastoma
14. 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)
15. 7. Unmethylated MGMT promoter status
16. 8. Maximum Eastern Cooperative Oncology Group (ECOG) score 2
17. 9. Estimated minimum life expectancy 3 months
18. 10. Stable or decreasing dose of corticosteroids during the week prior to inclusion
19. 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
20. 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)
21. 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
22. 10. Stable or decreasing dose of corticosteroids during the week prior to inclusion
23. 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
24. 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)
25. 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
26. 1. Written informed consent
27. 2. Age ≥18 years
28. 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.)
29. Expansion Group Arms D-H:
30. 1. Written informed consent
31. 2. Age ≥ 18 years
32. 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.)
33. 4. Patient agrees to subcutaneous port implantation
34. 5. Newly diagnosed, histologically confirmed, supratentorial WHO grade 4 glioblastoma, IDH-wildtype according to the 2021 World Health Organization Criteria for CNS tumors
35. 6. Status post incomplete resection (detectable residual tumor as per postoperative T1-weighted, contrast-enhanced MRI scan)
36. 7. Unmethylated MGMT promoter status
37. 8. Maximum Eastern Cooperative Oncology Group (ECOG) score 2
38. 9. Estimated minimum life expectancy 3 months
39. 10. Stable or decreasing dose of corticosteroids during the week prior to inclusion
40. 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 10E9/L and platelet count ≥ 100 x 10E9/L
41. 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)
42. 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 68

1. Dose Escalation Cohorts:
2. 3. Contra-indication or known hypersensitivity to MRI contrast agents, bevacizumab (Arm A only), olaptesed pegol or polyethylene glycol
3. 4. Planned hypofractionated radiotherapy
4. 1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
5. 5. Cytostatic therapy (chemotherapy) within the past 5 years
6. 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. 7. Secondary malignancy which is currently active
8. 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. 9. Prior radiotherapy to the head
10. 10. Any other previous or concomitant experimental glioblastoma treatments
11. 11. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
12. 9. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
13. 12. Patients with a history of arterial or venous thrombosis (or any other disease) requiring permanent intake of anticoagulants (Arm A only)
14. 13. Pregnancy or lactation
15. 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.
16. 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
17. 15. Prolongation of coagulation factors ≥ 2.5 x ULN (Arm A only)
18. 16. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
19. 17. Prior enrolment into this study
20. Expansion Group Arm C:
21. 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
22. 3. Contra-indication or known hypersensitivity to MRI contrast agents olaptesed pegol or polyethylene glycol or pembrolizumab (≥ Grade 3)
23. 10. Pregnancy or lactation
24. 4. Biopsy-only of GBM with less than 20% of tumor removed
25. 5. Presence of extracranial metastatic or leptomeningeal disease
26. 6. Severe hypersensitivity (≥ Grade 3) to other monoclonal antibodies
27. 7. Receiving immunosuppressive therapy
28. 3. Contra-indication or known hypersensitivity to MRI contrast agents, olaptesed pegol or polyethylene glycol
29. 8. Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agent
30. 9. Planned hypofractionated radiotherapy
31. 10. Cytostatic therapy (chemotherapy) within the past 5 years
32. 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)
33. 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
34. 11. 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
35. 13. Prior radiotherapy to the head
36. 14. Evidence of acute intracranial / intra-tumoral hemorrhage
37. 15. Any other previous or concomitant experimental glioblastoma treatments
38. 16. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
39. 17. Pregnancy or lactation
40. 4. Cytostatic therapy (chemotherapy) within the past 5 years
41. 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.
42. 19. Received a live vaccine within 30 days prior to the first dose of study drug.
43. 20. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Previously treated brain metastases may participate provided these remain stable
44. 21. Known history of HIV infection, hepatitis B or hepatitis C infection
45. 12. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
46. 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)
47. 23. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or current pneumonitis / interstitial lung disease
48. 24. Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (exceeding 10 mg daily of prednisone) or any other form of immunosuppressive therapy
49. 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
50. 26. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
51. 27. Prior enrolment into this study
52. 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)
53. 6. 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)
54. 7. Prior radiotherapy to the head
55. 8. Any other previous or concomitant experimental glioblastoma treatments
56. 13. Prior enrolment into this study
57. Expansion Group Arms D-H:
58. 1. Patients with tumors harboring IDH mutations
59. 2. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
60. 3. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days prior to screening visit or observation period of competing studies
61. 4. Contra-indication or known hypersensitivity to MRI contrast agents, bevacizumab, olaptesed pegol or polyethylene glycol
62. 5. Planned hypofractionated radiotherapy
63. 6. Chemotherapy (cytotoxic/cytostatic) within the past 5 years
64. 7. 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)
65. 8. Secondary malignancy which is currently active
66. Expansion Group Arms A and B:
67. 1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
68. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Safety (adverse events)

Secondary endpoints 19

1. Dose Escalation Cohorts und Expansion Group Arms A-C:
2. • PFS at 6 months (PFS-6)
3. • Median progression-free survival (mPFS)
4. • Median overall survival (mOS)
5. • Tumor vascularization as per vascular MRI scans at baseline and 2, 4, and 6 months
6. • Topography of recurrence
7. • Determination of maximum tolerated dose (MTD)
8. • Definition of recommended Phase 2 dose (RP2D)
9. • Olaptesed plasma levels at steady state
10. • NANO assessment
11. • Quality of Life
12. Expansion Group Arms D-H:
13. • PFS at 6 months (PFS-6)
14. • Median progression-free survival (mPFS)
15. • Median overall survival (mOS)
16. • Landmark overall survival at 18 months (OS18)
17. • Overall response rate (ORR)
18. • Olaptesed plasma levels at steady state
19. • Quality of Life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 12

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

TME Pharma AG

Sponsor organisation

TME Pharma AG

Address

Max-Dohrn-Strasse 8-10, Charlottenburg Charlottenburg

City

Berlin

Postcode

10589

Country

Germany

Scientific contact point

Organisation

TME Pharma AG

Contact name

Diede van den Ouden

Public contact point

Organisation

TME Pharma AG

Contact name

Diede van den Ouden

Third parties 5

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications