Set-up of the first pilot study on intraopertive 5-ALA PDT: INDYGO trial

Abstract

Nowadays, Glioblastoma Multiform (GBM) remains an incurable brain tumour despite of recent advances in the standard of care. Patients harboring newly diagnosed GBM, de novo GBM, undergo to surgery for maximal tumour resection followed by radiation ther-apy and concomitant and adjuvant chemotherapy (Temozolomide). This protocol has raised the overall survival to 14.5 months. Promis-ing results have been documented concerning 5-ALA interstitial photodynamic therapies. However, interstitial PDT has always been delivered to treat recurrent or non-operable tumours. Because of heterogeneous population of patients with different care protocols in the context of their relapsing disease or the absence of controlled clinical trial, efficacy of 5-ALA PDT is not still evidenced and thus not included in the standard protocol.In order to prove the 5-PDT efficacy on patients harboring de novo GBM, our group has developed a specific medical device to deliver PDT intraoperatively in the surgical cavity.The main idea is to benefit from the course of 5-ALA Fluores-cence Guided Resection (FGR) to achieve an illumination with the suitable wavelength (635 nm). Treatment of the infiltrating cells by a PDT effect is expected in the first millimeters of the surgical cavity. In such manner, intraoperative PDT is a simple add-on to the standard protocol that is more ethically acceptable and more efficient to assess PDT efficacy.Ten patients will be enrolled. Each patient will undergo standard treatment protocol including PDT early after surgery. 25 J/cm 2 will be delivered at 5 mm of the surgical cavity borders. A fractionation scheme will be applied: 5 fractions of 5 J/cm 2 each with off-period of 2 min between each fraction. A first early post-operative MRI will be acquired on the intraoperative MRI of our department. Then, MRI will be acquired quarterly to monitor the treatment response.The primary endpoint is the feasibility of intraoperative PDT, estimated by the proportion of patients who undergone intraoper-ative PDT without unacceptable toxicity. The expected objective is 70%, 7 of 10 patients that we plan to include. Secondary endpoints are progression-free survival (PFS), overall survival, and evalua-tion at 3 months, 6 months and 12 months of radiation treatment response and patients' quality of life. Finally, after the feasibility and the absence of adverse effects, our protocol will be experienced through a controlled multicenter clinical trial (Phase II) which will focus on dose escalation (light and 5-ALA) and new biomarkers findings. This multicenter clinical trial will be set-up and performed with the support of the European network Synaps (http://www. synaps-project.eu).

5‐ALA in the management of malignant glioma

“…If PDT is performed immediately following FGS, there would be no need for an additional drug application, as it has been shown in clinical pilot trials that timing and diagnostic dose of 5‐ALA (20 mg/kb bodyweight 4 to 6 hours prior to surgery) are sufficient and efficient for PDT in humans . A clinical pilot trial with this concept has been initiated in France . Irradiation is performed with a balloon diffuser, which is inserted into the surgical cavity.…”

5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas

“…After intraoperative MRI to assess the extent of surgical resection, PDT will be delivered as 5 fractions of 5 J/cm 2 separated by 2 min breaks in between fractions. Endpoints include toxicity assessment and analyses of survival and quality of life; immunological responses and biomarkers will be assessed [103,104].…”

Progress in Clinical Trials of Photodynamic Therapy for Solid Tumors and the Role of Nanomedicine

“…In 2019, Mahmoudi and his team published a comprehensive review that summarized five clinical trials that aimed to study the efficacy and safety of using 5-Aminolevulinic acid (5-ALA) with PDT in patients with high-grade gliomas (HGGs) [ 45 ]. A longer survival time was reported by the end of these studies [ 46 , 47 , 48 , 49 , 50 ], which were uncontrolled phase I and II studies with few participants. That was why the authors could not generalize the results or confirm the treatment’s safety.…”