Abstract B79: Translational study of tumor treating fields in combination with paclitaxel in ovarian cancer.
Authors: Munster Mijal , Blat Roni , Roberts Paul C. , Schmelz Eva M. , Giladi Moshe , Schneiderman Rosa S. , Porat Yaara , Bomzon Zeev , Urman Noa , Itzhaki Aviran , Voloshin Tali , Cahal Shay , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: May 2016

Abstract
Tumor Treating Fields (TTFields), a clinically active anticancer modality, are based on low intensity intermediate frequency alternating electric fields that exert their cytotoxicity by disrupting mitosis. The present study examines whether concomitant paclitaxel and TTFields have a beneficial impact on ovarian cancer growth both in vitro and in vivo. Moreover, on the basis of the preclinical observations, an open-label pilot clinical study evaluating the effect of the combined modalities in 30 patients with recurrent ovarian cancer was initiated.
Preclinical studies: To investigate the inhibitory effect of TTFields on ovarian cancer cell growth in vitro and determine optimal therapeutic frequency of TTFields in ovarian cancer, human ovarian cancer cell lines were treated with TTFields (100-400 kHz) for 72 hours using the inovitro system (Novocure, Haifa, Israel). To assess whether adding TTFields to paclitaxel increases the response of ovarian cancer cells to paclitaxel, we treated these cell lines with paclitaxel alone and in combination with TTFields. In vivo efficacy of the combined treatment was tested in female C57Bl/6 mice, orthotopically implanted with MOSE-L FFL luciferase positive cells. The feasibility of effective regional delivery of TTFields therapy to the ovaries, pelvis and abdomen of human subjects was examined using Finite Element Mesh (FEM) simulations performed using the Sim4life software. The FEM simulations demonstrated effective distribution of fields at intensities of 1-2 V/cm, which is above the minimal threshold required for TTFields response.
The INNOVATE Trial (NCT02244502): Based on positive preclinical studies demonstrating the combined efficacy of TTFields and paclitaxel in different ovarian cancer models, a pilot clinical trial was initiated to evaluate this therapeutic combination in recurrent ovarian carcinoma patients. In this prospective, pilot, single arm study, 30 patients will receive bi-directional TTFields at 200 kHz applied to the ovaries and surrounding intra-abdominal tissues using 4 transducer arrays located on the surface of the lower abdominal region. In addition, patients will receive concomitant paclitaxel at a standard regimen and dose. The combined treatment will be administered until further radiological progression. Inclusion criteria include ECOG score of 0-1 and no serious co-morbidities. The trial's primary endpoint is adverse events frequency and severity. The study will also collect preliminary efficacy data through the analysis of progression-free survival, 1-year survival rate and overall survival. Compliance data will be analyzed as an additional secondary endpoint. The INNOVATE study started to enroll patients in October 2014, and is currently accruing patients in Switzerland, Belgium and Spain. So far the trial has enrolled half of the planned 30 patients.
In summary, we present the first preclinical evidence in ovarian cancer of the combined efficacy of paclitaxel and TTFields, a new anticancer treatment modality. Our results suggest that it may represent a novel, effective therapeutic strategy against ovarian cancer. Pilot clinical testing is ongoing.
Citation Format: Mijal Munster, Roni Blat, Paul C. Roberts, Eva M. Schmelz, Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Zeev Bomzon, Noa Urman, Aviran Itzhaki, Tali Voloshin, Shay Cahal, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Translational study of tumor treating fields in combination with paclitaxel in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B79.