Radiodynamic Therapy (RDT) With Gliolan in Patients With First Recurrence of Brain Tumor (ALA-RDTinGBM)

Phase I/II Dose Escalation Trial of Radiodynamic Therapy (RDT) With 5-Aminolevulinic Acid in Patients With First Recurrence of Glioblastoma

The investigational drug 5-ALA (known under the trade name Gliolan®) is an approved drug for the surgical removal of malignant glioma (WHO grade III and IV). In this trial, the drug is being tested outside of its actual approval as a radiosensitizer in combination with conventional radiotherapy for first-time recurrence (relapse) of malignant glioma. In this clinical trial, the investigational drug 5-ALA is being used for the first time in a multiple dose escalation regimen in combination with radiotherapy following surgical removal of a recurrent malignant glioma in humans. The investigational drug, 5-ALA, has been used as a single dose to date as a standard of care for visualization of malignant tissue in the surgical removal of gliomas.

The planned clinical trial will first and foremost investigate how well repeated administration of the investigational drug 5-ALA is tolerated in combination with radiotherapy. At the same time, the design of the trial serves to optimize this novel therapeutic procedure with regard to the frequency of administration of the investigational drug 5-ALA in combination with radiotherapy for future clinical trials.

As a secondary objective, the efficacy of additional 5-ALA administration will also be investigated.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Gliolan; Radiation: Radiodynamic therapy

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Walter Stummer, Prof. Dr.; Phone Number: +49 251 8347472; Email: walter.stummer@ukmuenster.de
• Study Contact Backup: Name: Hans Theodor Eich, Prof. Dr.; Phone Number: +49 251 8347384; Email: hans.eich@ukmuenster.de

Study Locations

• Germany
  • Münster, Germany, 48149
    • Recruiting
    • University Hospital Münster, Klinik für Neurochirurgie
    • Contact: Walter Stummer, Prof. Dr.
    • Principal Investigator: Walter Stummer, Prof. Dr.
    • Sub-Investigator: Hans Theodor Eich, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written patient consent after comprehensive information
• Age >/= 18 years
• Recurrence of supratentorial glioblastoma after initial resection and adjuvant therapy (e.g. radio-chemotherapy, targeted therapies, antiangiogenic therapies as determined by the tumor board) (with planned second resection cohort 0 and 1), second or third recurrences permitted
• Clinically indicated further radiotherapy as per decision of the tumor board as part of therapy for recurrence
• Histological verification of recurrent glioblastoma independent of methylated MGMT promotor status when alkylating chemotherapy failed at this time.
• Karnofsky Performance Score ≥ 60

• For female and male patients and their female partners of childbearing/reproductive potential(*): Willingness to apply highly effective contraception (Pearl index <1) during the entire study (and for at least 6 months after the first application of 5-ALA). Such methods include:

  1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: I. oral II. intravaginal III. transdermal
  2. progestogen only hormonal contraception associated with inhibition of ovulation: I. oral II. injectable III. implantable
  3. intrauterine device (IUD)
  4. intrauterine hormone-releasing system (IUS)
  5. bilateral tubal occlusion
  6. vasectomised partner
  7. male patients have to use a condom
  8. sexual abstinence
• Pre-menopausal(*) female patients with childbearing potential: a negative pregnancy test must be obtained max. 72h prior to treatment start
• Adequate liver function: bilirubin < 1.5 times above upper limit of normal range (ULN), alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/SGOT) < 3 times ULN. In the case of documented or suspected Gilbert's disease bilirubin < 3 times ULN.
• Adequate renal function: creatinine < 3 times above ULN; eGFR >/= 60 ml/min, Blood clotting: INR/Quick/PT and PTT within acceptable limits according to the investigator.

(*) Definition: A man is considered of reproductive potential after puberty unless permanently sterile by bilateral orchidectomy. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Exclusion Criteria:

• Patient unable to undergo imaging by MRI, PET or contrast-enhanced CT for whatever reason (e.g. pace-maker)
• Pregnant and breastfeeding women
• Past medical history of diseases with poor prognosis, e.g., severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke, severe mental retardation or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
• Any active infection (at the discretion of the investigator)
• Hypersensitivity against porphyrins
• Known diagnosis of porphyria
• Participation in another clinical trial with therapeutic intervention or use of any other therapeutic interventional agent other than the standard therapy since diagnosis of glioblastoma
• Known intolerance to study medication
• Pre-treatment with other potentially phototoxic or photosensitizing substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts, products containing St. John's wort ) during the 2 weeks preceding RDT

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiodynamic therapy (RDT); All patients will be treated with RDT. Patients are devided into cohorts which differs in the total amount and frequence of RDT.	Drug: Gliolan; A repetitive dose of Gliolan will be administrated in combination with radiotherapy (radiodynamic therapy); Other Names: 5-Aminolevulinic acid; Radiation: Radiodynamic therapy; Radiotherapy will be performed in combination with Gliolan administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	In the resent study we will investigate the maximum-tolerated dose (MTD) of the combination of 5-ALA and radiation. MTD is defined as the highest number of RDT that does not cause unacceptable side effects, i.e. at which no more than 1 of 6 patients suffers a dose-limiting toxicity (DLT). DLT describes side effects of a drug that are serious enough to prevent an increase of dose (NCI dictionary of cancer terms). In the present study it is defined as any ≥ Gr.3 hematological toxicity, any ≥ Gr.3 neurological toxicity and any ≥ Gr.3 non-hematological toxicity occurring during the 6 week observation period, that does not resolve to pre-treatment baseline or ≤ Gr. 2 within 3 weeks, either spontaneously or with adequate treatment. To detect any relevant DLT the following aspects are monitored: Toxicological safety of repeat doses of 5-ALA; Neurological safety of RDT; Dermatological safety of RDT; Assess all new AEs CTCAE grade 2 or higher	6 weeks after last R(D)T in adjuvant phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival rate (OSR)	Percentage of patients who are alive 6 months after first R(D)T	6 months after first R(D)T in adjuvant phase
progression-free survival rate (PFS)	Percentage of patients without tumor progression 6 months after first R(D)T in adjuvant phase	6 months after first R(D)T in adjuvant phase
event-free survival rate (EFS)	Percentage of patients without suffering any disease related event such as DLT or progression until 6 months after inclusion	6 months after inclusion
concentration changes of immunhistochemistry marker (e.g. Caspase-3, IBA1, H&E, EvG, P53, Ki 67, gammaH2AX)	analytic results of pharma-radio-dynamic tissue changes. Tissue samples collected during surgery of cohort 0 and 1	during surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
concentration changes of CPI and CPIII	Analytic results for concentration changes as one combined sum parameter	6 months after first R(D)T in adjuvant phase
concentration changes of radiobiological marker CD3	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
concentration changes of radiobiological marker CD4	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
concentration changes of radiobiological marker CD8	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
concentration changes of radiobiological marker C19	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
concentration changes of radiobiological marker for total leucocyte count	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase

Collaborators and Investigators

• Sponsor: Universität Münster
• Collaborators: photonamic GmbH & Co. KG
• Investigators: Principal Investigator: Walter Stummer, Prof. Dr., University hospital Muenster

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: September 7, 2022
• First Submitted That Met QC Criteria: October 20, 2022
• First Posted (Actual): October 21, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 10, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Recurrence; Glioblastoma; Dermatologic Agents; Photosensitizing Agents; Aminolevulinic Acid
• Other Study ID Numbers: WWU20_0041; 2021-004631-92 (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
• product manufactured in and exported from the U.S.: No