ABSTRACT: Abstract Background We present a pre-specified interim analysis of an ongoing open-label, investigator-sponsored phase 1 trial (NCT02893137) testing safety/efficacy of a new rGBM treatment. The intervention combines personalized skull-remodeling (SR) surgery with TTFields and best-choice chemotherapy. SR-surgery involves minor craniectomy, burr-holes, and/or skull thinning personalized to enhance TTFields intensity focally in the tumor. Material and Methods Accrual began Dec 2016 (planned total 15 patients). Eligibility: Age > 18 years, first recurrence focal supratentorial GBM (RANO), and KPS ? 70. Personalized electric field calculations were conducted to validate TTFields enhancement > 25% by SR-surgery. Patients were right-censored for OS and PFS at the time of analysis and excluded upon progression, death, SUSARs, or unacceptable AEs. Primary endpoints: Toxicity (CTCAEv4.0). Secondary endpoints: OS, PFS, PFS6, objective response rate (iRANO), quality of life, KPS, and steroid dose. Results The interim analysis was based on data prior to April 1, 2018. Safety data were analyzed for all enrolled patients and efficacy for all patients treated with TTFields. 16 patients were screened, 1 declined, and 2 had KPS < 70. Of the 13 enrolled patients, 3 were excluded prior to TTFields treatment (1 female due to radionecrosis/non-recurrence, 1 male due to post-op infection, and 1 female due to neurodeficit). All included patients (9 male and 1 female) had GBM IDH-wt tumors (4 MGMT-methylated). Median KPS was 90 (range 70–100) and median age 55 years (range 49 to 67). All patients received maximum safe resection at recurrence (4 had no residual tumor (RANO), 4 had non-measurable disease, and 2 had measurable disease). 8 patients received adjuvant bevacizumab monotherapy (10 mg/kg every 2 weeks, median number of cycles 9.5, range 4 to 23) and 2 received temozolomide rechallenge (200 mg/m2 every 4 weeks, 3 and 4 cycles, respectively). The mean skull-defect area was 10.5 cm2 (range 7 to 24 cm2), the median field enhancement 37 % (range 25 to 61%), and the median TTFields compliance 91% (range 61 to 95%). Within the observation period 5 patients had progression, 3 died, 5 were censored for PFS, and 7 for OS. We observed no SUSARs or grade 4/5 SAEs, but 5 grade 3 SAEs (2 generalized seizures in patients with known epilepsy, 1 post-op infection, 1 diarrhea, and 1 DVT). 2 patients had grade 1–2 skin rash, and 1 had grade 1–2 headaches. Median OS was 15.5 months, 95%-CI: 5.9-NA, median PFS 9.5 months, 95%-CI: 3.7-NA, and PFS6 58%, 95%-CI: 0.27–0.90. 1 patient had complete response during TTFields treatment. Conclusion SR-surgery including craniectomy is not associated with additional toxicity in combination with TTFields and holds promising potential for improving TTFields outcome by focally enhancing the field intensity in the tumor. A future phase 2/3 trial is being planned for efficacy assessment.
