A pilot study to assess feasibility and safety of intraoperative 5-aminolevulinic acid mediated photodynamic (5-ALA PDT) therapy for the treatment of newly diagnosed glioblastoma (GBM)

Ongoing / closed: Active (enrollment completed, patients follow-up)

Research type (rétro/prospective): Prospective

Synopsis: Glioblastoma is the most infiltrative and aggressive primitive cerebral tumour (grade IV, WHO). Despite the armamentarium, including procedures such as maximal microsurgical resection followed by concomitant radio-chemotherapy following maintenance chemotherapy, patients with glioblastoma still experience a dismal prognosis, with a median survival of 15 months. Due to the invasive growth characteristics, 85% of GBM recurrence occurs within 2.5 cm of the postsurgical cavity. Thus, it is critical to improve local control of the disease. In this context, photodynamic therapy (PDT), using 5-aminolevulinic acid (5-ALA) - or talaporfin sodium-induced fluorescence, may be effective.

5-ALA PDT is a non-thermic technology based on the synergy of three elements: a photosensitizer, lighting at a precise wavelength and the presence of oxygen.5-ALA is a second-generation photosensitizer (PS) precursor that has been used in Europe since 2007 for fluorescence-guided resection. 5-ALA is a natural prodrug that is produced in the mitochondria of all human cells, with the exception of erythroblasts, which contain no mitochondria. After several enzymatic modifications that occur during heme biosynthesis and a final oxidation step, 5-ALA is transformed into Protoporphyrin IX (PpIX). PpIX is a photoactive compound (the true second-generation photosensitizer) with an absorption peak near 635 nm. Following such an excitation, two types of reactions highly toxic for tumour cells occur: the production of free radicals and oxygen species formation. 5-ALA has sufficient oral bioavailability and PPIX is highly selective for tumour tissue and presents a shorter skin photosensitization period in comparison to previous PS precursors.We propose a pilot trial to assess the feasibility of intraoperative  5-ALA mediated PDT in patients harboring glioblastoma and undergoing to surgical resection. This treatment will be achieved in addition to the current standard of care (i.e. Radiotherapy and Chemotherapy then Chemotherapy alone).

Principal Investigator: Pr. Nicolas Reyns (Neurosurgery Dpt - University Hospital of Lille - France)

Scientific coordinators: Dr. Maximilien Vermandel (University of Lille - France) - Pr. Serge Mordon (INSERM - France)

Study Sponsor: University Hospital of Lille - France

Primary endpoint: feasibility study of intraoperative photodynamic therapy  early after surgical resection of glioblastoma without unacceptable and unexpected toxicities

Secondary endpoints:

• Evaluation of the progression-free survival (PFS)
• Evaluation of the overall survival (OS)
• Evaluation of the treatment response on MRI
• Evaluation of the quality of life

Evaluation criteria of the primary endpoint: Assessment of  the feasibility of intraoperative PDT (after  4 hours preoperative administration of 5-ALA  and maximum surgical resection of the tumor bed), with a collection of unacceptable and unexpected toxicities ≥ Grade 3 (according to NCI-CTC V4.0) reviewed by a Independent Safety Committee up to 1 month after PDT.

Evaluation criteria of the secondary endpoints:

• PFS determined from the date of diagnosis of glioblastoma until relapse as defined by international standards (Revised Assessment in Neuro-Oncology -RANO- criteria),
• OS determined from the date of diagnosis of glioblastoma until the date of death,
• Response to treatment assessed by MRI exams every 3 months after  intraoperative PDT until recurrence,
• Quality of life assessed by questionnaires (QLQ-C30 and QLQ-BN20) pre- and post- PDT every 3 months until recurrence.

Estimated enrollment: 10 patients

Clinicaltrials.gov identifier: NCT03048240

Contact and location: University Hospital of Lille, France