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

Glioblastoma Clinical Trial

— ALA-RDTinGBM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05590689
• Other study ID #: WWU20_0041
• Secondary ID: 2021-004631-92
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 9, 2022
• Est. completion date: January 2025

Study information

• Verified date: December 2023
• Source: Universität Münster
• Contact: Walter Stummer, Prof. Dr.
• Phone: +49 251 8347472
• Email: walter.stummer[@]ukmuenster.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 34
• Est. completion date: January 2025
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma
• Recurrence

Intervention

Drug:
• Gliolan
A repetitive dose of Gliolan will be administrated in combination with radiotherapy (radiodynamic therapy)

Radiation:
• Radiodynamic therapy
Radiotherapy will be performed in combination with Gliolan administration

Locations

Country	Name	City	State
Germany	University Hospital Münster, Klinik für Neurochirurgie	Münster

Sponsors (2)

Lead Sponsor	Collaborator
Universität Münster	photonamic GmbH & Co. KG

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	concentration changes of radiobiological marker CD3	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
Other	concentration changes of radiobiological marker CD4	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
Other	concentration changes of radiobiological marker CD8	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
Other	concentration changes of radiobiological marker C19	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
Other	concentration changes of radiobiological marker for total leucocyte count	Analytic results for concentration changes	6 months after first R(D)T in adjuvant phase
Primary	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	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
Secondary	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
Secondary	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
Secondary	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