A Dose-escalation Clinical Study of Intraoperative Photodynamic Therapy of Glioblastoma

The primary objective of this clinical trial is to determine the safety and tolerability of two doses of light in intraoperative PDT added to standard of care; temozolomide-based chemotherapy in male and female patients aged 18 to 75 with newly diagnosed glioblastoma.

This treatment will be carried out in addition to the maximal surgical resection. Data collected during this trial will be used to design the upcoming pivotal study .

The study will utilize an independent Data and Safety Monitoring Board (iDSMB) that will review safety data to allow dose escalation.

This study is a non randomized, open label, single center , phase 1/2 trial with a sequential enrollment in a 3+3 dose escalation design to establish the maximal tolerated dose of light (MTD).

The dose of light will be escalated in successive cohorts of patients until at least 1 patient experiences a dose-limiting toxicity (DLT).

A DLT is defined as any grade ≥ 3 Adverse Event (AE), or any relevant grade 2 AE of Central Nervous System or any Serious Adverse Events (SAEs) possibly, probably or definitively related to the intraoperative PDT (i.e., 5-aminolevulinic acid hydrochloride (5-ALA HCl) administration + brain cavity illumination), for which the onset date is within 28 days after the procedure, and where conservative therapy fails and surgical is required, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

After dose escalation patient will be followed in the standard of care until visit at 6 months to evaluate the progression free survival.

Eligibility Criteria:
Inclusion criteria

1. Males or females must be between 18, or legal age of consent, and 75 years of age (both included) at the time of signing informed consent.
2. Signed informed consent which includes compliance with requirements and restrictions listed in the informed consent.
3. Newly diagnosed GBM (grade IV malignant high-grade glioma), presumed on the basis of clinical and MRI criteria (intra-axial brain tumor with peripheral rim contrast enhancement)
4. Karnofsky Performance Scale ≥ 70
5. Eligible for surgery
6. Amenable to maximal tumor resection based on MRI.
7. Planned to receive SOC (i.e., Stupp Protocol) treatment after surgery.
8. Ability to take oral medications.

Exclusion criteria

1. Patients with radiographic tumors of/or involving unresectable midline, basal ganglia, or brain stem as assessed by MRI
2. Patients with prior brain surgery other than stereotactic biopsy 2. Patient with Lynch syndrome 3. Patient with Li-Fraumeni syndrome 4. Debilitating cardiopulmonary disease, unstable Type 1 or Type 2 diabetes (treated or not) 5. History or current condition of another malignancy (excluding basal cell carcinoma, or carcinoma in-situ) unless treated and off all active therapy for more than 5 years 6. Clinically significant abnormal ECG results, including a corrected QT interval QTc \> 480 ms 7. Creatinine clearance \< 60 mL/min 8. Severe hepatic impairment (bilirubin \> 1.5 x the upper limit of normal \[ULN\] or alkaline phosphatase or transaminases (AST, ALT) \> 2.5 x ULN) 9. Known allergic reactions to silicone 10. Known allergic reactions or hypersensitivity to egg, soya, or peanut proteins.

   11. Febrile illness 12. Contraindication to 5-ALA HCl administration, including:

a. Porphyria b. Taking photosensitizing drugs 24 hours before and 14 days after the administration of Pentalafen® including but not limited to: St. John's wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines, andtopical preparations containing ALA c. Inability to suspend a long-term hepatotoxic treatment (such as, but not limited to diclofenac, fenofibrate, carbamazepine) for 24 hours after 5-ALA HCl intake 13. Contraindication to MRI examination (e.g., MRI-incompatible pacemaker) 14. Treatment with another investigational drug or intervention within 30 days prior to or during the entire study 15. Predictable non-compliance with the rules for preventing the transient risk of skin photosensitization.

16. Clinical follow up not possible for psychological, family, social, or geographic reasons.

17. Legal incapacity 18. Pregnancy or lactation 19. Women of childbearing potential (WOCBP) and males with WOCBP partners not willing to use an effective contraceptive method from inclusion until end of study.