389 Combination Therapy With Paclitaxel, Carboplatin, and Low-Intensity Ultrasound for Recurrent Glioblastoma: Rationale for Ongoing Phase II Clinical Trial

Abstract

INTRODUCTION: We recently participated in Phase 1/2 clinical trials where patients with recurrent glioblastoma received surgery for resection of the tumor followed by implantation of an ultrasound device (SonoCloud-9, Carthera, Lyon, France) into a window in the skull for subsequent repeated blood-brain barrier (BBB) opening and concomitant delivery of chemotherapy. Intraoperative experiments demonstrated a 4-6-fold increase in the brain concentration of paclitaxel (NCT04528680) and carboplatin (NCT03744026) after BBB disruption. METHODS: We analyzed the cytotoxicity of paclitaxel and carboplatin in vitro against five human cell lines and six patient-derived xenografts (PDX) as monotherapy and in combination at concentrations derived from our human intraoperative pharmacokinetic studies. Synergy was assessed using the Loewe model and survival benefit was evaluated in two xenografts where drugs were delivered with ultrasound. We also examined the effects on cell cycle progression, DNA damage, and apoptosis. RESULTS: Cell lines exhibited non-overlapping susceptibility to paclitaxel and carboplatin, with 27% being exclusively susceptible to one drug. The combination covered 81% of cell lines, demonstrating synergy in 55% of cell lines. Notably, paclitaxel, carboplatin, and ultrasound proved more effective than monotherapy in two xenograft models. Combination therapy led to distinct effects on cell cycle progression and enhanced DNA damage and apoptosis. CONCLUSIONS: Combination therapy may be more effective than monotherapy, as has been shown in other cancers, due to synergy and independent susceptibility to each drug in glioma cell lines. This strategy is currently under investigation in an ongoing phase II clinical trial to further evaluate the safety and efficacy of this approach in patients with recurrent glioblastoma (NCT04528680).