A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma,British Journal of Cancer

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A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma
British Journal of Cancer ( IF 6.4 ) Pub Date : 2023-07-24 , DOI: 10.1038/s41416-023-02356-1
Juanita Lopez ₁ , Julia Lai-Kwon ₁ , Rhoda Molife ₁ , Liam Welsh ₁ , Nina Tunariu ₁ , Desamparados Roda ₁ , Paula Fernández-García ₂ , Victoria Lladó ₂ , Adrian G McNicholl ₂ , Catalina A Rosselló ₂ , Richard J Taylor ₂ , Analía Azaro ₃ , Jordi Rodón ₃ , Julieann Sludden ₄ , Gareth J Veal ₄ , Ruth Plummer ₄ , Ander Urruticoechea ₅ , Ainhara Lahuerta ₅ , Karmele Mujika ₅ , Pablo V Escribá ₂

Affiliation

Background

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.

Methods

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).

Results

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.

Conclusions

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.

Clinical trial registration

EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.

中文翻译：

羟基油酸的 1/2A 期试验：一流的鞘脂调节剂和神经胶质瘤细胞自噬诱导剂，对难治性神经胶质瘤具有抗肿瘤活性

背景

一流的脑穿透性合成羟基化脂质异羟基油酸（2-OHOA；2-羟基油酸钠）可激活鞘磷脂合酶表达并调节膜脂组成和线粒体能量产生，诱导癌细胞自噬。我们报告了 2-OHOA 的多中心首次人体 1/2A 期试验 (NCT01792310) 的结果，确定了最大耐受剂量 (MTD) 并评估了安全性和初步疗效。

方法

我们进行了一项开放标签、非随机试验，以评估 54 名神经胶质瘤和其他晚期实体瘤患者每日口服 2-OHOA 单药治疗 (BID/TID) 的安全性、耐受性、药代动力学、药效学和抗肿瘤活性。使用标准 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 上进行了两个扩展队列以确定推荐的 2 期剂量 (RP2D)。

结果

总共有 32 名复发患者被纳入剂量递增阶段（500-16,000 毫克/每日）。2-OHOA 随剂量成比例的暴露而被迅速吸收。治疗总体耐受性良好，最常见的治疗相关不良事件 (AE) 为可逆的 1-2 级恶心、呕吐和腹泻。4 名患者出现恶心、呕吐、腹泻等胃肠道剂量限制性毒性 (DLT)（3 名患者服用 16,000 mg，1 名患者服用 12,000 mg），建立 RP2D 剂量为 12,000 mg/天。在复发性高级别神经胶质瘤 (HGG) 患者中观察到潜在活性。在接受剂量递增和扩展治疗的 21 名 HGG 患者中，5 名 (24%) 获得了临床获益（RANO CR、PR 和 SD > 6 个周期），其中 1 名特殊缓解持续 > 2.5 年。