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

Study Overview
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Brief Summary
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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 69 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.

Detailed Description
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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.

Official Title
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An Interventional, Non-randomized, Phase 1/2, Light Dose-escalation Study to Investigate the Safety and Feasibility of Intraoperative Photodynamic Therapy (PDT) With Pentalafen® Drug and Heliance®Solution Device in Male and Female Patients 18 to 69 Years of Age With Grade IV Glioblastoma

Conditions
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Primary Glioblastoma

Intervention / Treatment
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* Combination Product: 5-ALA HCl intraoperative Photodynamic Therapy (PDT) at 200 J/cm^2
* Combination Product: 5-ALA HCl intraoperative Photodynamic Therapy (PDT) at 400 J/cm^2


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Males or females must be between 18, or legal age of consent, and 69 years of age (inclusive) at the time of signing informed consent. Signed informed consent which includes compliance with requirements and restrictions listed in the informed consent. 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) Karnofsky Performance Scale ≥ 60 Eligible for surgery Amenable to maximal tumor resection based on MRI. Planned to receive SOC (i.e., Stupp Protocol) treatment after surgery. Ability to take oral medications. Exclusion criteria Patients with radiographic tumors of/or involving unresectable midline, basal ganglia, or brain stem as assessed by MRI. Patient with Lynch syndrome Patient with Li-Fraumeni syndrome Debilitating cardiopulmonary disease Any history of cancer Clinically significant abnormal ECG results, including a corrected QT interval QtCf > 480 ms. Creatinine clearance < 60 mL/min Severe hepatic impairment (bilirubin > 1.5 x the upper limit of normal [ULN] or alkaline phosphatase or transaminases (AST, ALT) > 2.5 x ULN) Known allergic reactions to silicone. Known allergic reactions or hypersensitivity to egg, soya, or peanut proteins. Febrile illness Contraindication to 5-ALA HCl administration, including: Porphyria Taking photosensitizing drugs 24 hours before administration of Pentalafen® Inability to suspend a long-term hepatotoxic treatment for 24 hours after 5-ALA HCl intake. Contraindication to MRI examination (e.g., pacemaker or metallic foreign body) Treatment with another investigational drug or intervention within 30 days prior to or during the entire study Predictable non-compliance with the rules for preventing the transient risk of skin photosensitization. Clinical follow up not possible for psychological, family, social, or geographic reasons. Legal incapacity Pregnancy or lactation Women of childbearing potential (WOCBP) and males with WOCBP partners not willing to use an effective contraceptive method from inclusion until end of study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 model.The dose of light will be escalated in successive cohorts of patients. The starting dose is at 200 J/cm2. Enroll 3 patients at the first dose level and proceed to the next higher dose level with a cohort of 3 patients until at least 1 patient experiences a dose-limiting toxicity (DLT).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 200 J/cm^2<br>Patient will undergo intraoperative Photodynamic therapy at 200 J/cm^2 | Combination Product: 5-ALA HCl intraoperative Photodynamic Therapy (PDT) at 200 J/cm^2<br>* 5-ALA HCl, 20 mg/kg, is orally administered 4-6 hours before the surgery. Then after resection of tumor tissue is judged maximal, the intraoperative PDT procedure is initiated at 200 J/cm^2.<br>* Other names: 5-ALA PDT;|
| Experimental: 400 J/cm^2<br>Patient will undergo intraoperative Photodynamic therapy at 400 J/cm^2 | Combination Product: 5-ALA HCl intraoperative Photodynamic Therapy (PDT) at 400 J/cm^2<br>* 5-ALA HCl, 20 mg/kg, is orally administered 4-6 hours before the surgery. Then after resection of tumor tissue is judged maximal, the intraoperative PDT procedure is initiated at 400 J/cm^2.<br>* Other names: 5-ALA PDT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Tolerated Dose (MDT) of light for Photodynamic Therapy | Evaluation of Dose Limiting Toxicities (DLT) to define MDT | 4 weeks after intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment response / Progression-free survival (PFS) | MRI imaging and RANO criteria | Up to 6 months after intervention | 
| Number of Adverse Events and Serious Adverse Events (Safety and Tolerability) | Global clinical safety data of 5-ALA HCl Intraoperative PDT | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioma, Glioblastoma, High Grade Glioma