Clinical and translational controlled study of Perampanel treatment around Surgery in patients with progressive glioblastoma (PerSurge)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Heidelberg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Jan 2024 → ongoing

Decision date (initial)

2023-11-30

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BMBF

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

The primary aim of the trial is to demonstrate the efficacy of pre-surgical perampanel compared
to placebo treatment with respect to
A) the shift of mRNA expression patterns to a lower connectivity score in tumour tissue,
and
B) the presurgical tumour growth rate as assessed by tumour volume [cm³] per a central blinded
independent review committee (BIRC) based on AI-quantified MRI parameters (T2/FLAIRweighted
images)
in patients with recurrent/progressive glioblastoma willing to adhere to the randomised treatment
and who will undergo surgery.

Secondary objectives 8

1. kinetics in contrast-enhancing (T1CE images) tumour volume by central AI-based MRI assessment per BIRC [pre-surgical; postsurgical ]
2. kinetics in tumour volume (T2/FLAIR) by central AI-based MRI assessment per the BIRC [postsurgical]
3. health-related quality of life (HRQoL) and symptoms as assessed by the EORTC QLQ-C30 and QLQ-BN20 patient questionnaires,
4. severity of cognitive impairment as assessed by the mini-mental state examination (MMSE)
5. overall survival (OS)
6. progression-free survival (PFS) (from randomisation until progression according to RANO criteria)
7. epileptic seizure activity
8. To check for the occurrence of the adverse effects reported in the summary of the medical product characteristics (SmPC) of the drug and to compare between both treatments.

Conditions and MedDRA coding

Progressive Glioblastoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Histologically confirmed glioblastoma, progressive or recurrent after 1 or 2 lines of prior treatment, involving one radiotherapy and drug treatments according to institutional standards or prior trial participation, >3 months after end of radiotherapy, and therapy for relapse not yet started.
2. Indication for surgical resection of progressive or recurrent tumour tissue, with a safe waiting interval of up to 5 weeks.
3. A sufficient amount of resected tumour tissue (minimum 0.5 cm3) is expected to be available for the trial-specific molecular, morphological, functional and perampanel level analysis.
4. Tumour progression according to RANO criteria
5. Age ≥18 years
6. Karnofsky Performance status score (KPS) ≥ 60%
7. Life expectancy > 3 months
8. Willing and able to comply with regular neurocognitive and health-related quality of life tests/questionnaires.
9. Written informed consent
10. Cognitive state to understand rationale, necessity and individual consequences of study therapy and procedures.
11. Female patients with reproductive potentiala must use an approved contraceptive method during and for 4 weeks after the end of trial medication (Pearl Index <1%)
12. Female patients with reproductive potential: a negative serum pregnancy test (beta- HCG) must be obtained prior to treatment start.

Exclusion criteria 17

1. Participation in other ongoing interventional clinical trials.
2. Inability to undergo contrast-enhanced MRI.
3. Inability to undergo surgery (e.g. because of need for continuous anticoagulation, known bleeding disorders, thrombocytopenia <50/nl, pre-existing wound healing problems).
4. Any continued or planned standard or experimental treatment for the tumour other than resection, including antiangiogenic therapy (such as Bevacizumab), and local therapy in addition to the planned resection, including BCNU wafers, loco-regional hyperthermia, tumour bed irradiation, and photodynamic therapy.
5. Tumour carries a known mutation in the IDH1 or IDH2 gene
6. Severe or significant abnormal (≥ Grade 3 CTCAE v5.0) laboratory values for haematology (Hb, WBC, neutrophils, or platelets), liver (serum bilirubin, ALT, or AST) or renal function (serum creatinine).
7. Known active tuberculosis; HIV infection or active Hepatitis B (HBV) or Hepatitis C (HCV infection, or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients’ blood or tissue (e.g. rabies).
8. Any prior treatment with perampanel
9. Contraindication against treatment with perampanel
10. Concomitant intake of enzyme-inducing antiepileptic drugs (EIAEDs: carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidon, rufinamid)
11. Steroid intake of more than 4 mg dexamethasone (or equivalence dose) in the last week, or expected indication for it in the foreseeable future
12. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within the last 2 years unless the patient has been disease-free for 2 years.
13. Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study.
14. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry.
15. Pregnancy or breastfeeding
16. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
17. The presence of any other concomitant severe, progressive, or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, or psychiatric disease, or signs or symptoms thereof, that may affect the subject’s participation in the study, according to investigators judgement.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. A) Connectivity score determined in RNA Seq from tumour tissue (tumour cryosamples)
2. B) Kinetics in T2/FLAIR signal abnormality volume by central AI-based MRI assessment per BIRC [from baseline to pre-surgical resection]

Secondary endpoints 8

1. pre-surgical and post-surgical log-transformed tumour volume [cm³] per the BIRC based on AIquantified MRI parameters (T1CE images) [day 0 to day 30 prior to surgery; post-surgical: POD0 to POD30]
2. post-surgical log-transformed tumour volume [cm³] per the BIRC based on AI-quantified MRI parameters, incorporating the volumes from peri-tumoral T2/FLAIR signal abnormality, excluding those areas showing ischemia (based on DWI) [on immediate postoperative MRI to day 60 post-randomisation, i.e. POD0-3 to POD30]
3. EORTC QLQ-C30, QLQ-BN20: absolute change from baseline at POD30 in the C30 summary score (according to EORTC manual; with higher scores indicating worse symptoms)
4. MMSE: absolute change from baseline at POD30 in total MMSE score.
5. OS defined as the time from the date of randomisation to the date of death due to any cause.
6. imaging-based PFS defined as time from date of randomisation to date of first documented radiographic progression (according to the RANO criteria37,38 and Appendix A2) which include observer-blinded MRI-based assessments and clinical stability) or date of death due to any cause, whichever occurs first.
7. total number of epileptic seizures (irrespective of severity and duration) between baseline and POD30
8. occurrence of side effects (AE, SAE, SUSARs) until 3 days after end of treatment (adverse events will be coded using MedDRA).

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Heidelberg AöR

Sponsor organisation

Universitaetsklinikum Heidelberg AöR

Address

Im Neuenheimer Feld 672, Neuenheim Neuenheim

City

Heidelberg

Postcode

69120

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

Prof. Dr. Frank Winkler

Public contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

Prof. Dr. Frank Winkler

Locations

1 EU/EEA country · 13 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 6 files

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

Application history

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