Abstract CT067: 2-hydroxyoleic acid (2-OHOA), a novel activator of sphingomyelin synthase with antitumor activity in refractory glioblastoma: results of the first-in-human dose-escalation (DE) study in patients with advanced solid tumors (AST) and refractory gliomas/glioblastomas
Authors: Lopez Juanita S. , Fontes Mariane , Coleman Niamh , Azaro Analia , Drew Yvette , Escriba Pablo , Busquets Xavier , Veal Gareth , Tur Vicenc , Perier Antoine , Sicart Elisabet , Molife Rhoda , Plummer Ruth , Rodon Jordi 
Published: July 2016

Abstract
Background: 2-OHOA, is a synthetic hydroxylated lipid that activates sphingomyelin synthase and regulates the lipid content of cell membranes resulting in translocation of Ras to the cytoplasm and inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. 2-OHOA causes autophagic cell death of glioma cell lines in vitro, and reduces tumor growth in numerous xenograft mice models including glioblastoma (GBM), prostate, leukemia, breast and colon cancer. It also crosses the blood brain barrier. This first-in-human trial was designed to determine the safety, tolerability, and recommended phase 2 dose (RP2D), alongside the pharmacokinetic (PK), pharmacodynamic (PD) and anti-tumor profile of 2-OHOA.
Methods: Eligible pts with AST or GIII/IV gliomas/glioblastomas received 2-OHOA as a daily PO suspension in 21 day cycles using a 3+3 DE design. Adverse events (AE) were assessed by CTCAEv4; Tumor response was assessed every 2 cycles using RECIST 1.1/RANO criteria.
Results: 32 pts were enrolled on the DE stage. 28 pts were evaluable for safety (13 gliomas and 15 AST). Pts were treated with doses from 500mg-16g/day in 7 cohorts. Drug-related AEs &gt;Grade 3 of nausea, vomiting and diarrhea (n = 6) were seen at high doses. DLTs were diarrhea (n = 3) and vomiting (n = 1) at 12 and 16g/day. Extent of exposure (AUC) was generally proportional to the dose. The PK profile showed dose accumulation from 8g/day. Average t1/2 ranged
from 1-2h to 8-12h with longer half-lives seen at higher doses Steady state was reached with 12 and 16g/day. 4 pts had clinical benefit for &gt;6mo, 25% of refractory GBM patients treated (3/12) had objective responses by RANO criteria : 1 partial response (PR) and 2 stable disease (SD). The GBM pt with confirmed PR was treated at 1g/daily for 41 cycles and continues on treatment; the other 2 GBM pts were treated at 12g/day and had SD for 9 cycles.
Conclusions: The MTD and RP2D of 2-OHOA is 12g/daily. Clinical benefit was observed in 4 pts including durable responses in 25% of advanced treatment-refractory GBM pts treated. Recruitment is ongoing including an expansion cohort for advanced gliomas/glioblastomas. Clinical trial information: NCT01792310
Citation Format: Juanita S. Lopez, Mariane Fontes, Niamh Coleman, Analia Azaro, Yvette Drew, Pablo Escriba, Xavier Busquets, Gareth Veal, Vicenc Tur, Antoine Perier, Elisabet Sicart, Rhoda Molife, Ruth Plummer, Jordi Rodon. 2-hydroxyoleic acid (2-OHOA), a novel activator of sphingomyelin synthase with antitumor activity in refractory glioblastoma: results of the first-in-human dose-escalation (DE) study in patients with advanced solid tumors (AST) and refractory gliomas/glioblastomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT067.