Clinical Safety Study on 5-Aminolevulinic Acid (5-ALA) in Children and Adolescents With Supratentorial Brain Tumors

In this prospective, open, single-armed, multicenter, phase II study for application of 5-ALA in children and adolescents with supratentorial brain tumors 80 patients will be investigated.

Primary objective of the study is to determine the safety of 5-ALA for fluorescence-guided resections in children and adolescents with supratentorial, intra-axial brain tumors.

Secondary objectives are

• to determine whether fluorescent tissue truly signifies tumor (positive predictive value) in various pediatric brain tumors
• to determine the degree of tumor resection on early post-operative MRI
• and to determine the pharmacokinetics of 5-ALA in this population.

Study Overview

• Status: Recruiting
• Conditions: Brain Tumor, Pediatric
• Intervention / Treatment: Drug: 5-Aminolevulinic Acid Hydrochloride, Oral

Detailed Description

In 2007, 5-aminolevulinic acid (5-ALA) was approved in Europe by the European Medicines Agency (EMA) (brand name: Gliolan®) for "the visualization of malignant tissue during surgery for malignant glioma (WHO III and IV) in adults." Similarly, approval for 5-ALA was granted by the FDA in 2017 as an "optical imaging agent indicated in patients with gliomas (suspected World Health Organization Grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery" (brand name: Gliolan®). Goal of the study is to investigate if the use of 5-ALA is safe in children and get preliminary information on the type of paediatric brain tumors which are suitable for fluorescence-guided resection with 5-ALA.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Schwake, Dr.; Phone Number: 47484 /47472 +49 251 83; Email: Michael.Schwake@ukmuenster.de
• Study Contact Backup: Name: Walter Stummer, Prof. Dr.; Phone Number: 47472 +49 251 83; Email: Walter.Stummer@ukmuenster.de

Study Locations

• Germany
  • Augsburg, Germany, 86146
    • Recruiting
    • Universitätsklinikum Augsburg, Klinik für Neurochirurgie
    • Contact: Ehab Shiban, PD Dr.
    • Principal Investigator: Ehab Shiban, PD Dr.
    • Sub-Investigator: Björn Sommer, PD Dr.
  • Essen, Germany, 45147
    • Recruiting
    • Universitätsklinikum Essen, Klinik für Neurochirurgie
    • Contact: Philip Dammann, Prof.
    • Principal Investigator: Philip Dammann, Prof.
    • Sub-Investigator: Yahya Ahmadipour, PD Dr.
  • Mainz, Germany, 55131
    • Recruiting
    • Universitätsmedizin Mainz, Klinik und Poliklinik für Neurochirurgie
    • Contact: Florian Ringel, Prof.
    • Contact: Malte Ottenhausen, Dr.
    • Principal Investigator: Florian Ringel, Prof.
    • Sub-Investigator: Malte Ottenhausen, Dr.
  • München, Germany, 81377
    • Recruiting
    • Neurochirurgische Klinik der Universität München (LMU)
    • Contact: Niklas Thon, PD Dr.
    • Principal Investigator: Niklas Thon, PD Dr.
    • Sub-Investigator: Kunz Mathias, Dr.
  • Münster, Germany, 48149
    • Recruiting
    • University Hospital Münster, Klinik für Neurochirurgie
    • Contact: Michael Schwake, Dr.
    • Principal Investigator: Walter Stummer, Prof.
    • Sub-Investigator: Michael Schwake, Dr.
  • Tübingen, Germany, 72076
    • Recruiting
    • Universitätsklinikum Tübingen, Klinik für Neurochirurgie
    • Contact: Martin Schumann, Prof.
    • Principal Investigator: Martin Schuhmann, Prof.
    • Sub-Investigator: Constantin Roder, PD Dr.
• Netherlands
  • Utrecht, Netherlands, 3584
    • Recruiting
    • Prinses Máxima Centrum voor kinderoncologie BV
    • Contact: Kirsten van Baarsen, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 3 - <18 years
• First radiological diagnosis of intra-axial, supratentorial contrast-enhancing tumor on MRI or recurrent supratentorial intra-axial brain tumor (malignant glioma, astrocytoma, malignant ependymoma, atypical teratoid rhabdoid tumors (AT/RT), Oligodendroglioma, etc.)
• Resection is part of therapeutic strategy with an emphasis on neurological safety
• Informed consent by the parents or guardians and if possible assent of the patient after education of purpose and risks of study. Patients that are able to understand should provide assent to participate in the trial
• Female adolescents: not pregnant (pregnancy test required for adolescents of child-bearing age) and not breast-feeding (for at least 24 hours after Gliolan intake). Female patients of childbearing potential and male patients who are sexually active must be practising a highly effective method of birth control up to 6 weeks after the tumor operation consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials.

Exclusion Criteria:

• Posterior fossa tumors
• Extra-axial tumors such as craniopharyngioma
• Germ cell tumor or entities precluding surgical resection
• Acute or chronic porphyria
• Hypersensitivity to 5-ALA or porphyrins
• Renal insufficiency: serum creatinine > 2x upper limit of normal (ULN)
• Hepatic insufficiency: serum bilirubin > 2x ULN, serum γ-glutamyl transferase > 2,5 x ULN, alanine transaminase (ALT) and aspartate transaminase (AST)> 2,5 ULN
• Blood clotting: INR (international normalized ratio) out of acceptable limits
• Other malignant disease
• Patients with pre-existing cardiovascular diseases
• Co-administration with other potentially phototoxic substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts)
• Planned administration of potentially hepatotoxic substances within 24 hours after 5-ALA administration

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5-Aminolevulinic Acid (5-ALA); Application of 5-ALA oral solution followed by fluorescence-guided brain tumor resection	Drug: 5-Aminolevulinic Acid Hydrochloride, Oral; Application of 5-ALA oral solution (20mg/kg bw) 4 hours (range 3.5-4.5 hours) prior to anesthesia followed by fluorescence-guided tumor resection Tumor resection is performed conventionally using a surgical microscope. A change from white light to blue light is possible at anytime to make the fluorescence visible; Other Names: Gliolan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of 5-ALA for fluorescence-guided resections in children and adolescents determined as incidence of adverse events of CTCAE grade III-V.	Incidence of adverse events of CTCAE grade III, IV or V (excluding chemotherapy-associated toxicities) during and after 5-ALA fluorescence-guided resections in children and adolescents	up to 6 weeks after tumor resection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
True positive rate of fluorescence for indicating tumor	Biopsies will be taken during tumor resection. The true positive rate of 5 ALA induced fluorescence for three different tumor regions, i.e. the number of fluorescing tumor samples containing tumor cells divided by the number of all tumor samples from 1) the tumor bulk, 2) the border area and 3) the suspected infiltration zone. A stratification will be performed depending on whether surgery is for newly diagnosed or recurrent tumor.	Day 0: during the surgery
Determination of the percentage of patients with gros total resection and subtotal resection	For every patient in whom a complete resection of enhancing tumor is expected a priori, it will be assessed whether there is residual contrast-enhancement or not on early post-operative MRI. The volume of contrast-enhancing tumor on early post-operative MRI (up to 72h after surgery) in cm3 will be determined. If the volume is < 0.175cm3, the patient will be classified as "gros total resection". If the volume is >0.175cm3, the patient will be classified as "subtotal resection". Percentage of patients for both groups will be determined.	up to 72h after surgery
Correlation of residual contrast-enhancing tumor with residual fluorescence after surgery	For both groups (patients with gros total and subtotal resection) the percentage of patients with residual fluorescence at end of surgery, as determined during the surgery by the operating surgeon (yes/no), will be calculated.	Day 0: during the surgery
Determination of protoporphyrin IX (PPIX) in serum to analyse AUC (Area under the curve) of PPIX	The investigators aim to determine 5-ALA pharmacokinetics in children and adolescents from PPIX plasma levels in order to assess if the pharmacokinetics differ between adults and children. Pharmacokinetic data will be analyzed using population pharmacokinetic software approach using nonlinear-mixed effects modelling (NONMEM). In order to assess if the pharmacokinetics are similar, the area under the curve (AUC) for PPIX as a measure of 5-ALA exposure will be calculated. For this purpose protoporphyrin IX will be measured in serum 3 times within 12h after 5-ALA-administration.	3-6 hours, 6-9 hours and 9-12 hours after surgery
Determination of protoporphyrin IX (PPIX) in serum to determine interpolated maximum plasma concentration (Cmax) of PPIX.	Protoporphyrin IX will be measured in serum 3 times within 12h after 5-ALA-administration. Pharmacokinetic data will be analyzed using population pharmacokinetic software approach using nonlinear-mixed effects modelling (NONMEM). Using the model, interpolated maximum plasma concentration (Cmax) of PPIX will be determined for every patient.	3-6 hours, 6-9 hours and 9-12 hours after surgery

Collaborators and Investigators

• Sponsor: Westfälische Wilhelms-Universität Münster
• Collaborators: photonamic GmbH & Co. KG; medac GmbH
• Investigators: Principal Investigator: Walter Stummer, Prof., University Hospital Muenster

Publications and helpful links

General Publications

• Schwake M, Schipmann S, Muther M, Kochling M, Brentrup A, Stummer W. 5-ALA fluorescence-guided surgery in pediatric brain tumors-a systematic review. Acta Neurochir (Wien). 2019 Jun;161(6):1099-1108. doi: 10.1007/s00701-019-03898-1. Epub 2019 Apr 13.

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2020
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: May 13, 2020
• First Submitted That Met QC Criteria: February 3, 2021
• First Posted (Actual): February 4, 2021

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: pediatric; 5-ALA; supratentorial; intra-axial; Fluorescence-guided resection
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Neoplasms; Photosensitizing Agents; Dermatologic Agents; Aminolevulinic Acid
• Other Study ID Numbers: UKM2013_0034; 2014-005669-54 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No