Stereotactical Photodynamic Therapy With 5-aminolevulinic Acid (Gliolan®) in Recurrent Glioblastoma

Study Overview
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Brief Summary
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In this multicenter, randomized, non-blinded trial the efficacy and safety of stereotactical photodynamic therapy with 5-aminolevulinic acid will be investigated in 106 patients with recurrent glioblastoma.

Official Title
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Controlled Clinical Trial to Evaluate the Safety and Efficacy of Stereotactical Photodynamic Therapy With 5-aminolevulinic Acid (Gliolan®) in Recurrent Glioblastoma

Conditions
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Glioblastoma Multiforme, Adult

Intervention / Treatment
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* Drug: Stereotactic biopsy followed by stereotactical photodynamic therapy with 5-aminolevulinic acid
* Procedure: Stereotactic biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age 18 - 75 years Karnofsky Performance Score (KPS) of ≥60 % Radiologically suspected diagnosis (according to RANO criteria) of the first recurrence of a glioblastoma located in the cerebral hemisphere including insular and diencephalon. Tumors in the brain stem are excluded. First MRI with signs of first recurrence (radiologic RANO criteria for disease progression) within 8 weeks prior to Informed Consent. Not necessarily identical to primary tumor location Single or single progressive contrast-enhancing lesion on MRI, largest diameter not more than 2.5 cm For female and male patients of reproductive potential: Willingness to apply highly effective contraception (Pearl index <1) during the entire study Exclusion Criteria: Multifocal disease > 2 locations Patients with significant non-enhancing tumor portions Previous treatment of recurrence Other malignant disease except basalioma Hypersensitivity against porphyrins or Gliolan® or Fluorethylenpropylen (FEP ) Porphyria HIV infection, active Hepatitis B or C infection Bone marrow reserve: white blood cell (WBC) count <2000/μl, platelets <100000/μl, Liver function: total bilirubin > 1.5 times above upper limit of normal range (ULN) alanine transaminase (ALT) and aspartate transaminase (AST) > 3 times ULN Renal function: - creatinine > 1.5 times ULN Blood clotting: - Quick/INR or PTT out of acceptable limits Conditions precluding MRI (e.g. pacemaker) Past medical history of diseases with poor prognosis, e.g. severe coronary heart disease, heart failure (NYHA III/IV), severe 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) Any psychological, cognitive, familial, sociological or geographical condition that, in the investigator's opinion, compromises the patient's ability to understand the patient information, to give informed consent or to comply with the trial protocol Previous antiangiogenic treatment Participation in another interventional clinical trial during this trial or within 4 weeks before entry into this trial. Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Stereotactic biopsy followed by stereotactical photodynamic therapy | Drug: Stereotactic biopsy followed by stereotactical photodynamic therapy with 5-aminolevulinic acid<br>* 5-ALA HCl orally (20 mg/kg bw) 3,5-4,5 hours prior to induction of anaesthesia for stereotactic biopsy followed by stereotactical photodynamic therapy. All patients will receive further treatment of recurrent glioblastoma at the investigator´s discretion (best possible care).<br>* Other names: Gliolan, 5-aminolevulinic acid;|
| Other: Control arm<br>Stereotactic biopsy | Procedure: Stereotactic biopsy<br>* Stereotactic biopsy. All patients will receive further treatment of recurrent glioblastoma at the investigator´s discretion (best possible care).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Progression free survival (PFS) measured as time from the day of randomization until diagnosis of progressive disease as determined by MRI according to RANO criteria (Response Assessment in Neuro-Oncology Criteria) or death from any cause | through study completion (at least 1.5 years and a maximum of 5 years) or until progression or death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month PFS rate | Progression free survival (PFS) measured as time from the day of randomization until diagnosis of progressive disease as determined by MRI according to RANO criteria or death from any cause | for each patient up to 6 months after randomization or until progression has occurred | 
| Overall survival (OS) | Overall survival (OS) measured as time from the day of randomization until death | through study completion (at least 1.5 years and a maximum of 5 years) or until death | 
| Progression free time | Progression free time as time from the day of randomization until progressive disease (death is regarded as censored) | through study completion (at least 1.5 years and a maximum of 5 years) or until progression | 
| 12-month OS rate | Overall survival (OS) measured as time from the day of randomization until death | for each patient up to 12 months after randomization or until death | 
| Absolute changes from baseline in contrast medium volume uptake from the MRI performed 48 hours after randomization on, and during any MRI performed thereafter to monitor for disease progression |  | Baseline, 26 - 48 hours after stereotactic procedure, 1 month after randomization and then every 2 months, 1.5 years after randomization or at disease progression, and then every 3 months until end of entire study (up to 5 years) or progression | 
| 48h response rate on MRI (Complete Remission, Partial Remission, Stable Disease) after treatment with iPDT (interstitial photodynamic therapy) | Response is assessed according to the RANO criteria | 26 - 48 hours after stereotactic procedure in patients treated with interstitial photodynamic therapy (iPDT) | 
| If a PET (positron emission tomography) was performed less than 2 weeks apart from an MRI: Consistency of both procedures with regard to the region of interest (ROI) |  | Baseline, 26 - 48 hours after stereotactic procedure, 1 month after randomization and then every 2 months, 1.5 years after randomization or at disease progression and then every 3 months until end of entire study (up to 5 years) or progression | 
| Change in KPS (Karnofsky Performance Score) | Minimum value: 0, maximum value: 100. A higher value means a better outcome. | Baseline, 26 -48 hours after stereotactic procedure, upon discharge or 7 days after stereotactic procedure, 1 month after randomization and then every 2 months until 1.5 years after randomization or disease progression | 
| Change in NIHSS (National Institutes of Health Stroke Scale) | Minimum value: 0, maximum value: 42. A higher value means a worse outcome. | Baseline, 26 -48 hours after stereotactic procedure, upon discharge or 7 days after stereotactic procedure, 1 month after randomization and then every 2 months until 1.5 years after randomization or disease progression | 
| Change in MMSE (Mini-Mental State Examination) | Minimum value: 0, maximum value: 30. A higher value means a better outcome. | Baseline, 26 -48 hours after stereotactic procedure, upon discharge or 7 days after stereotactic procedure, 1 month after randomization and then every 2 months until 1.5 years after randomization or disease progression | 
| Brain edema as assessed by MRI within 26 to 48 h after stereotactic surgery |  | 26 to 48 hours after stereotactic intervention | 
| Frequency of Adverse Events |  | over the entire study period of each patient (at least 1.5 years and a maximum of 5 years) | 
| Change in the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire) score during study participation |  | Baseline, at discharge or 7 days after intervention, 1 month after randomization and then every 2 months, 1.5 years after randomization or at disease progression and then every 3 months until end of entire study (up to 5 years) or progression | 
| Change in the EORTC QLQ-BN20 module (European Organisation for Research and Treatment of Cancer Quality of Life Brain Cancer Module) score during study participation |  | Baseline, at discharge or 7 days after intervention, 1 month after randomization and then every 2 months, 1.5 years after randomization or at disease progression and then every 3 months until end of entire study (up to 5 years) or progression |