Background: Tumor Treating Fields (TTFields), a non-invasive, loco-regional, anti-mitotic treatment comprises low-intensity alternating electric fields. In the phase III EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival compared to TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This pilot study [NCT03780569] evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for ≥18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) in combination with daily TMZ (75 mg/m²). In the adjuvant phase, patients received monthly TMZ (150–200 mg/m² for 5 days) plus TTFields. The primary outcome was safety of the combined therapies; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were graded per CTCAE v4.0. Results: Ten patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median Karnofsky Performance Score was 90.0, and eight (80%) patients were male. Five (50%) patients had undergone tumor resection while the remainder had biopsy only. Eight patients experienced ≥1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced ≥1 AE. Three patients suffered from serious AEs (urinary tract infection, confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in eight (80%) patients; all were of low severity (CTCAE grade 1–2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. Conclusions: Eighty percent of patients experienced grade 1–2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed and there was no increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Based on the safety and preliminary efficacy results of this pilot study, a phase 2 randomized trial (N = 60; NCT03869242) and the Phase 3 TRIDENT trial have been initiated to further investigate the efficacy of concomitant RT/TMZ/TTFields in ndGBM. Clinical trial information: NCT03780569