P05.03 OptimalTTF-1: Final results of a phase 1 study at first glioblastoma recurrence examining targeted craniotomy to enhance Tumor Treating Fields intensity
Authors: A R Korshøj, N Mikic, S Lukacova, J C H Sørensen, F L Hansen, A Thielscher, S O S Cortnum, T L Guldberg, Y Ramshad-Lassen, C Rahbek, K E Severinsen, G von Oettingen
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND OptimalTTF-1 is an open-label phase-1 study on the combination of Tumor Treating Fields (TTFields) treatment together with targeted skull remodeling surgery aiming to enhance the electric field intensity in the brain (NCT02893137). Skull-remodeling surgery (SR-surgery) in this trial aims to reduce the electrical impedance of the skull. Pre-clinical modeling experiments indicate that these procedures may increase the intensity of the applied electric field. The final analysis this trial examined primarily toxicity of (TTFields) in combination with SR-surgery and best-choice chemotherapy in first glioblastoma recurrence (rGBM). MATERIAL AND METHODS 15 patients (4 female and 11 male) were enrolled into the trial, which was active from December 2016 to March 2019. The primary endpoint was frequency of serious adverse events (CTCAEv4.0) and among the secondary endpoints were overall survival (OS) and progression-free survival (PFS).Eligible patients were ≥18 years of age, had focal supratentorial rGBM, a KPS ≥60, and a minimum increase in TTFields i by ≥25% after SR-surgery, which was afterwards verified by computation field calculations. At the time-of-analysis patients were censored for time-to-event endpoints. RESULTS The baseline data (median (range)) demonstrated a patient age of 57 (39;67), skull defect area= 10.6 cm2 (7;37), and an increase in the TTFields intensity by 43% (25;59). All of the examined GBM tumors were IDH-wt and 4 of them carried an MGMT-Promoter methylation. In total, 4 patients were excluded from the study because of the following reasons: withdraw of consent, radionecrosis/non-recurrence, postoperative infection and neurodeficit, prior to treatment start. 11 patients (2 female/9 male) were treated with the study procedure.Headache 60% CI95%= [32; 84], fatigue 53%, CI95%= [27; 79], skin rash 47%, CI95%= [21; 73], and nausea 40%, CI95%= [16; 68] were found to be the most common AE of grade 1–2. With respect to grade 3 SAE, 6 seizures, 1 headache, 1 fatigue, 1 TIA, 1 post-op infection, 1 diarrhea and 1 DVT were observed. However, no device- related serious adverse events (SAEs) or grade 4–5 were reported. With respect to the secondary endpoints of OS and PFS, the study revealed that the PFS6 was 64%, CI95%= [35; 85], PFS= 8.8 months, CI95%= [6.2; 13.2], OS= 15.0 months, CI95%= [9.6;16.2], and OS12= 64%, CI95%= [35;85].The treatment compliance was 90% (48; 98) and the mean treatment duration was 6.8 months (2.3; 20.4). CONCLUSION The results of this study demonstrate that targeted craniotomy combined with TTFields is safe and does not induce additional toxicity. Therefore, this treatment regimen, by increasing the intensity of the electric field, could potentially result in significant improvement of overall survival in patients suffering from recurrent glioblastoma. Further evaluation of this concept in a phase 2 clinical trial is currently being planned.