The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK.
Laminar Pharmaceuticals, Palma de Mallorca, Spain.
Br J Cancer. 2023 Sep;129(5):811-818. doi: 10.1038/s41416-023-02356-1. Epub 2023 Jul 24.
The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy.
We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D).
In total, 32 recurrent patients were enrolled in the dose-escalation phase (500-16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1-2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years.
2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies.
EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.
第一类穿透大脑的合成羟化脂质 idroxioleic 酸（2-OHOA； 2-羟基油酸钠），可激活鞘磷脂合酶的表达，并调节膜脂质组成和线粒体能量产生，诱导癌细胞自噬。我们报告了一项多中心、首例人体 1/2A 期试验（NCT01792310）的结果，该试验评估了 2-OHOA 的最大耐受剂量（MTD），并评估了安全性和初步疗效。
我们进行了一项开放性、非随机试验，评估了每日口服 2-OHOA 单药治疗（BID/TID）在 54 例胶质瘤和其他晚期实体瘤患者中的安全性、耐受性、药代动力学、药效学和抗肿瘤活性。采用标准的 3+3 设计进行剂量递增阶段，以确定安全性和耐受性。随后在 MTD 下进行两个扩展队列，以确定推荐的 2 期剂量（RP2D）。
共有 32 例复发性患者入组剂量递增阶段（500-16000mg/天）。2-OHOA 吸收迅速，暴露量呈剂量依赖性。总的来说，治疗耐受性良好，最常见的治疗相关不良事件（AE）为可逆性 1-2 级恶心、呕吐和腹泻。4 例患者出现胃肠道剂量限制性毒性（DLT），包括恶心、呕吐和腹泻（3 例患者为 16000mg，1 例患者为 12000mg），确定 12000mg/天为 RP2D。在复发性高级别胶质瘤（HGG）患者中观察到潜在的活性。在接受剂量递增和扩展的 21 例 HGG 患者中，5 例（24%）具有临床获益（RANO CR、PR 和 SD >6 个周期），1 例异常反应持续>2.5 年。
2-OHOA 在这一治疗困难的恶性脑肿瘤患者人群中表现出良好的安全性和令人鼓舞的活性，使其成为治疗胶质瘤和其他实体瘤恶性肿瘤的理想候选药物。
EudraCT 注册号：2012-001527-13；Clinicaltrials.gov 注册号：NCT01792310。
