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

Study Overview
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Brief Summary
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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.

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

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Gliolan
* Radiation: Radiodynamic therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written patient consent after comprehensive information Age between 18 and 75 years First local recurrence (no remote lesion) of supratentorial glioblastoma after standard therapy (surgery, radio-chemotherapy, concomitant + adjuvant TMZ), second surgery completed, except for neo-adjuvant cohort 0 and 1 Clinically indicated second radiotherapy Histological verification of recurrent glioblastoma, non-methylated MGMT promotor Karnofsky Performance Score ≥ 70 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) Other invasive malignancy within 2 years (except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured) 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

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
Intervention Model: Sequential Assignment
Interventional Model Description: A modified 3+3 design is used. The maximum tolerated dose of repeated RDT (consisting of 5-ALA dosing an radiotherapy) and safety will be determined in 9 cohorts.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |