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

Primary Purpose

Brain Tumor, Pediatric

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

5-Aminolevulinic Acid Hydrochloride, Oral

About this trial

This is an interventional diagnostic trial for Brain Tumor, Pediatric focused on measuring 5-ALA, supratentorial, intra-axial, Fluorescence-guided resection, pediatric

Eligibility Criteria

3 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Universitätsklinikum Augsburg, Klinik für NeurochirurgieRecruiting
Universitätsklinikum Essen, Klinik für NeurochirurgieRecruiting
Universitätsmedizin Mainz, Klinik und Poliklinik für NeurochirurgieRecruiting
Neurochirurgische Klinik der Universität München (LMU)Recruiting
University Hospital Münster, Klinik für NeurochirurgieRecruiting
Universitätsklinikum Tübingen, Klinik für NeurochirurgieRecruiting
Prinses Máxima Centrum voor kinderoncologie BVRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

5-Aminolevulinic Acid (5-ALA)

Arm Description

Application of 5-ALA oral solution followed by fluorescence-guided brain tumor resection

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT04738162

First Posted

May 13, 2020

Last Updated

November 28, 2022

Sponsor

Westfälische Wilhelms-Universität Münster

Collaborators

photonamic GmbH & Co. KG, medac GmbH

1. Study Identification

Unique Protocol Identification Number

NCT04738162

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 25, 2020 (Actual)

Primary Completion Date

April 2023 (Anticipated)

Study Completion Date

April 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Westfälische Wilhelms-Universität Münster

Collaborators

photonamic GmbH & Co. KG, medac GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Brain Tumor, Pediatric

Keywords

5-ALA, supratentorial, intra-axial, Fluorescence-guided resection, pediatric

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

5-Aminolevulinic Acid (5-ALA)

Arm Type

Experimental

Arm Description

Application of 5-ALA oral solution followed by fluorescence-guided brain tumor resection

Intervention Type

Drug

Intervention Name(s)

5-Aminolevulinic Acid Hydrochloride, Oral

Other Intervention Name(s)

Gliolan

Intervention Description

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

Primary Outcome Measure Information:

Title

Safety of 5-ALA for fluorescence-guided resections in children and adolescents determined as incidence of adverse events of CTCAE grade III-V.

Description

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

Time Frame

up to 6 weeks after tumor resection

Secondary Outcome Measure Information:

Title

True positive rate of fluorescence for indicating tumor

Description

Time Frame

Day 0: during the surgery

Title

Determination of the percentage of patients with gros total resection and subtotal resection

Description

Time Frame

up to 72h after surgery

Title

Correlation of residual contrast-enhancing tumor with residual fluorescence after surgery

Description

Time Frame

Day 0: during the surgery

Title

Determination of protoporphyrin IX (PPIX) in serum to analyse AUC (Area under the curve) of PPIX

Description

Time Frame

3-6 hours, 6-9 hours and 9-12 hours after surgery

Title

Determination of protoporphyrin IX (PPIX) in serum to determine interpolated maximum plasma concentration (Cmax) of PPIX.

Description

Time Frame

3-6 hours, 6-9 hours and 9-12 hours after surgery

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Michael Schwake, Dr.

Phone

+49 251 83

Ext

47484 /47472

Michael.Schwake@ukmuenster.de

First Name & Middle Initial & Last Name or Official Title & Degree

Walter Stummer, Prof. Dr.

Phone

+49 251 83

Ext

47472

Walter.Stummer@ukmuenster.de

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Walter Stummer, Prof.

Organizational Affiliation

University Hospital Muenster

Official's Role

Principal Investigator

Facility Information:

Facility Name

Universitätsklinikum Augsburg, Klinik für Neurochirurgie

City

Augsburg

ZIP/Postal Code

86146

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ehab Shiban, PD Dr.

First Name & Middle Initial & Last Name & Degree

Ehab Shiban, PD Dr.

First Name & Middle Initial & Last Name & Degree

Björn Sommer, PD Dr.

Facility Name

Universitätsklinikum Essen, Klinik für Neurochirurgie

City

Essen

ZIP/Postal Code

45147

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Philip Dammann, Prof.

First Name & Middle Initial & Last Name & Degree

Philip Dammann, Prof.

First Name & Middle Initial & Last Name & Degree

Daniela Pierscianek, Dr.

Facility Name

Universitätsmedizin Mainz, Klinik und Poliklinik für Neurochirurgie

City

Mainz

ZIP/Postal Code

55131

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Florian Ringel, Prof.

First Name & Middle Initial & Last Name & Degree

Malte Ottenhausen, Dr.

First Name & Middle Initial & Last Name & Degree

Florian Ringel, Prof.

First Name & Middle Initial & Last Name & Degree

Malte Ottenhausen, Dr.

Facility Name

Neurochirurgische Klinik der Universität München (LMU)

City

München

ZIP/Postal Code

81377

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Niklas Thon, PD Dr.

First Name & Middle Initial & Last Name & Degree

Niklas Thon, PD Dr.

First Name & Middle Initial & Last Name & Degree

Bogdana Suchorska, PD Dr.

Facility Name

University Hospital Münster, Klinik für Neurochirurgie

City

Münster

ZIP/Postal Code

48149

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michael Schwake, Dr.

First Name & Middle Initial & Last Name & Degree

Walter Stummer, Prof.

First Name & Middle Initial & Last Name & Degree

Michael Schwake, Dr.

Facility Name

Universitätsklinikum Tübingen, Klinik für Neurochirurgie

City

Tübingen

ZIP/Postal Code

72076

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Martin Schumann, Prof.

First Name & Middle Initial & Last Name & Degree

Martin Schuhmann, Prof.

First Name & Middle Initial & Last Name & Degree

Constantin Roder, PD Dr.

Facility Name

Prinses Máxima Centrum voor kinderoncologie BV

City

Utrecht

ZIP/Postal Code

3584

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kirsten van Baarsen, Dr.

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

30989383

Citation

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.

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

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