PANOVA-3: A phase 3 study of Tumor Treating Fields combined with nab-paclitaxel and gemcitabine for front-line treatment of locally-advanced pancreatic adenocarcinoma - Trial in progress
Authors: U. Weinberg, O. Faber, M. Giladi, Z. Bomzon, G. Lavy-Shahaf, E. Kirson
Journal: Annals of Oncology (2018)

Introduction: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality that predominantly acts by disrupting the formation of the mitotic spindle during metaphase. TTFields are delivered at specific frequencies (150 to 200 KHz) to the tumor region through transducer arrays placed on the skin surface. TTFields (200 KHz) are approved for the treatment of patients with recurrent and newly diagnosed glioblastoma. The effectiveness of TTFields has been demonstrated in multiple preclinical models of pancreatic cancer. TTFields in vitro showed a significant decrease in pancreatic adenocarcinoma cell count, an increase in cell volume and reduced clonogenicity. TTFields in vivo studied either alone or in combination with gemcitabine and paclitaxel in hamsters bearing syngeneic, orthotopic pancreatic tumors significantly reduced tumor volume. The Phase 2 PANOVA study [NCT01971281], the first trial of TTFields (150 KHz) in pancreatic cancer patients, demonstrated the safety of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and locally advanced pancreatic cancer (LAPC). Dermatitis was seen below the arrays: Grades 1-2 and 3-4 in 15% and 10% of patients respectively. The median progression-free survival (PFS) with TTFields + gemcitabine + nab-paclitaxel was 12.7 months (95% CI 5.4, NA). The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy and safety of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Methods: Patients (N = 556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients will have an ECOG score of 0-2 and no prior progression or treatment. Patients, stratified based on their performance status and geographical region will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2 once weekly). TTFields at a frequency of 150 kHz will be delivered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Transducer arrays are placed on the back and front of the patient to deliver the highest field intensities to the abdominal region. Follow up to be performed q8w, will include a CT scans of the chest and abdomen. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint. PFS, objective response rate, rate of resectability, quality of life and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%.