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.

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:
  3. oral II. injectable III. implantable
  4. intrauterine device (IUD)
  5. intrauterine hormone-releasing system (IUS)
  6. bilateral tubal occlusion
  7. vasectomised partner
  8. male patients have to use a condom
  9. 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