Background: Tumor Treating Fields (TTFields) are a novel, locoregional antimitotic treatment modality approved for glioblastoma and malignant pleural mesothelioma. Continuous, non-invasive low intensity, intermediate frequency (150–200 kHz) alternating electric fields are delivered to the tumor via skin-placed arrays. Invitro, TTFields (150 kHz), with or without chemotherapy, induced antiproliferative and anticlonogenic activity on pancreatic cancer cell lines (Giladi M, et al. Pancreatology 2014;14:54–63). The phase 2 PANOVA study (NCT01971281) demonstrated that the combination of TTFields with nab-paclitaxel and gemcitabine (GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) (Rivera F, et al. Pancreatology 2019;19:64–72). These data indicate that TTFields with GnP warrant phase 3 evaluation. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, phase 3 trial designed to investigate the efficacy and safety of TTFields concomitant with GnP in patients with LAPC. Planned enrollment is 556 patients. Eligibility criteria include unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region, and randomly assigned 1:1 to TTFields plus GnP or GnP alone. Based on a recent protocol amendment, a smaller and lighter-weight (reduced from 6 to 2.7 lbs) TTFields device will be used. Standard doses of nab-paclitaxel (125 mg/m²) and gemcitabine (1000 mg/m²) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria in Solid Tumors V1.1. Follow-up will be performed every 4 weeks and a computed tomography scan of the chest and abdomen every 8 weeks. After local disease progression, patients will be followed every month until death. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size was estimated per log-rank test comparing time to event in patients treated with TTFields plus GnP with published clinical trial data on patients treated with GnP alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. The trial is currently recruiting at 106 sites in Austria, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and USA. The DMC last reviewed the trial in August 2021, and suggested that the trial continue as planned. Clinical trial information: NCT03377491.