Enhancing Tumor Treating Fields for Recurrent Glioblastoma With Targeted and Individualised Skullremodeling Surgery: A Multi-center Randomized Phase 2 Trial

Introduction Tumor treating fields (TTFields) are low-intensity (1-3 v/m) intermediate frequency (200 khz for GBM) alternating fields that disrupt cell division. The treatment is increasingly used as a supplementary modality for patients with glioblastoma (GBM). Recent randomized clinical studies have demonstrated tolerability of TTFields (Optune®, Novocure®) for both newly diagnosed and recurrent GBM and a significant and sustained survival benefit in the former population. Specifically, the addition of TTFields to maintenance temozolomide (TMZ) therapy for newly diagnosed GBM patients, who had completed initial concurrent radio-chemotherapy, resulted in significantly prolonged median progression-free survival (PFS = 6.7 vs. 4.0 months, p<0.001) and median overall survival (OS = 20.9 vs. 16.0 months, p<0.001) compared to maintenance TMZ therapy alone (ef-14 trial) (4). Consequently, TTFields were recently approved by the US FDA and included as a category 1 recommendation in the most recent guidelines from the National Comprehensive Cancer Network (NCCN) for the treatment of newly diagnosed GBM. For recurrent GBM, TTFields monotherapy has been shown to have equivalent efficacy and a superior toxicity profile compared to best practice medical oncological therapy. This led to US FDA approval for this indication in 2011. In addition, a post-hoc analysis of the EF-14 dataset has indicated that the addition of TTFields to 2nd line medical oncological treatment at first disease recurrence leads to an overall survival benefit. Finally, the pride dataset showed that the addition of TTFields to current practice of medical oncological treatment was beneficial.

Recently, the investigators proposed a novel approach to calculate the electrical field distribution induced by TTFields therapy of GBM. The approach utilizes finite element analysis and incorporates personalized MRI data to provide a realistic and individualized estimate of the field intensity distribution, which is associated with the antimitotic efficacy of the treatment. Using this approach, the investigators showed that targeted skull-remodeling surgery, e.g. craniectomy or multiple burr-holes, can provide a substantial and highly focused enhancement (~100%) of the median field intensity in supratentorial tumors, while leaving the field distribution in healthy tissues unaffected.

These results support the theoretical rationale that small and clinically feasible craniectomies may improve the clinical efficacy of TTFields for cerebral hemispheric tumors without compromising patient safety. Based on these findings, the investigators recently concluded an open-label, single arm, prospective phase 1 trial (NCT02893137) to investigate safety and feasibility of SR-surgery with TTFields and best practice neuro-oncological therapy for recurrent GBM. The trial was active from December 2016 to May 2019. The planned total number of patients was fifteen. Eligibility criteria included age > 18 years, first recurrence focal supratentorial GBM (RANO), and KPS ≥ 70. Patients were right-censored for OS and PFS at the time of analysis and excluded upon progression, death, SUSARs, or unacceptable AEs. The primary endpoint was toxicity (CTCAEv4.0). The secondary endpoints were OS, PFS, PFS rate at six months (PFS6), objective response rate (ORR) based on the iRANO criteria (14), quality of life (QoL), Karnofsky performance score (KPS), and steroid dose.20 patients were screened, 2 declined, and 3 had KPS < 70. Of the 15 enrolled patients, 4 were excluded prior to TTFields due to radionecrosis/non-recurrence, post-op infection, neurodeficit and withdrawal of consent, respectively. All included patients (11 male and 2 female) had GBM IDH-wt tumors (4 MGMT-methylated). Median KPS was 90 (range 70-100) and median age 57 years (range 39 to 67). All patients received maximum safe resection at recurrence (4 had no residual tumor (RANO), 5 non-measurable disease, and 2 measurable disease). 9 patients received adjuvant bevacizumab monotherapy and 2 temozolomide rechallenge. The mean skull-defect area was 10.6 cm2 (range 7 to 37 cm2) and the median field enhancement 43 % (range 25 to 59%). The median follow-up duration was 10 months and the median TTFields compliance 90% (range 48 to 98%). We observed no SUSARs, no grade 4/5 SAEs, 12 grade 3 SAEs (6 generalized seizures in patients with known epilepsy, 1 post-op infection, 1 diarrhea, 1TIA, 1 fatigue, 1 headache and 1 DVT). The most common grade AE 1-2 was headache 60% CI95%= [32; 84], fatigue 53%, CI95%= [27; 79], skin rash 47%, CI95%= [21; 73], and nausea 40%, CI95%= [16; 68].

Regarding survival results were 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]. One patient had complete response during TTFields. Based on these results, the investigators concluded that skull-remodelling surgery incl. craniectomy is not associated with additional toxicity in combination with TTFields and best practice medical oncological treatment and holds promising potential for improving TTFields outcome by focally enhancing the field intensity in the tumor. The proposed phase 2 trial aims to validate this hypothesis in a randomized comparative setting.

METHODS AND ANALYSIS Trial design The study is designed as an investigator-initiated, prospective, multi-center, multi-national, randomized, minimax two-stage, comparative, phase 2 trial, investigating superior efficacy of the intervention. Patients randomized to the control arm will receive TTFields plus best physician's choice medical oncological treatment (BPC treatment) and patients in the interventional arm will receive SR-surgery in addition to TTFields and BPC treatment. The trial will enroll an expected sample size of 70 patients from 4-6 scandinavian countries with Aarhus University Hospital, Denmark, as the Sponsor and coordinating site. The primary outcome will be overall survival at 12 months (OS12) and the trial is designed to detect a 20% increase in OS12 in the interventional arm compared to control (from 40% in the control arm to 60% in the interventional arm). Secondary outcomes will include progression-free survival (PFS), quality of life (QoL), clinical performance, and objective response rate (ORR). Interim futility analysis will be conducted after 12 months follow-up of the first 52 patients. The trial will be stopped at interim analysis if the OS12 months is lower in the control arm compared to the interventional arm. The trial design and data reporting is in accordance with the consort 2010 statement, the gnosis standards for neuro-oncology trials, recent RANO recommendations for phase 2 trial design in neuro-oncology, and general recommendations for phase 2/3 trial design (16-19). The study will be performed in the period march 2020 to march 2023. The inclusion period is expected to be the first 24 months of the trial.