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

Official title

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

Overview

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.

Interventions

• 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

Primary outcome measures

• Maximum tolerated dose (MTD) [Time frame: 6 weeks after last R(D)T in adjuvant phase]

Secondary outcome measures (4)

• Overall survival rate (OSR) [Time frame: 6 months after first R(D)T in adjuvant phase]
• progression-free survival rate (PFS) [Time frame: 6 months after first R(D)T in adjuvant phase]
• event-free survival rate (EFS) [Time frame: 6 months after inclusion]
• concentration changes of immunhistochemistry marker (e.g. Caspase-3, IBA1, H&E, EvG, P53, Ki 67, gammaH2AX) [Time frame: during surgery]

Eligibility criteria

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:

• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: I. oral II. intravaginal III. transdermal
• progestogen only hormonal contraception associated with inhibition of ovulation: I. oral II. injectable III. implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomised partner
• male patients have to use a condom
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 1 center

• University Hospital Münster, Klinik für Neurochirurgie — Münster

Publications

• Pepper NB, Eich HT, Muther M, Oertel M, Rehn S, Spille DC, Stummer W. ALA-RDT in GBM: protocol of the phase I/II dose escalation trial of radiodynamic therapy with 5-Aminolevulinic acid in patients with recurrent glioblastoma. Radiat Oncol. 2024 Jan 22;19(1):11. doi: 10.1186/s13014-024-02408-7. PMID 38254201

Identifiers

NCT: NCT05590689 · WWU20_0041 · 2021-004631-92

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗