IntherUnit, Hospital Clínic i Provincial de Barcelona, Barcelona, Catalonia, Spain.
Department of Medical Oncology, Hospital Clinic, Barcelona Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain.
Eur J Cancer. 2021 Mar;146:87-94. doi: 10.1016/j.ejca.2020.12.019. Epub 2021 Feb 12.
ABTL0812 is an autophagy inducer that promotes cancer cell death by activation of cytotoxic autophagy selectively in tumour cells. ABTL0812 induces endoplasmic reticulum stress and blocks the Akt-mTOR axis; both actions converge to activate a robust and sustained autophagy leading to cancer cell death. Preclinical data supported the initiation of clinical trials in patients with cancer.
This first-in-human trial consisted of an escalation phase (3 + 3 design), followed by an expansion phase, to assess safety and tolerability of ABTL0812. Secondary objectives were determining the recommended phase II dose (RP2D), clinical antitumour activity, pharmacokinetics (PK) and pharmacodynamics (PD).
A total of 29 patients were enrolled and treated; fifteen patients were treated in four escalation dosing cohorts (ranging from 500 mg once a day to 2000 mg twice a day) and fourteen in the expansion phase (dosed with 1300 mg three times a day). No maximum tolerated dose was attained, and RP2D was determined by PK/PD modelling. Most drug-related adverse events were gastrointestinal grade I-II. Correlation between drug levels and pAkt/Akt ratio was found. Two cases of long-term (>1 year) stable disease were observed.
ABTL0812 is safe and has an acceptable tolerability profile, allowing a long-term oral dosing. RP2D of 1300 mg three times a day was determined according to PK/PD modelling, and preliminary antitumour efficacy was observed.
NCT02201823.
ABTL0812 是一种自噬诱导剂，通过在肿瘤细胞中选择性激活细胞毒性自噬来促进癌细胞死亡。ABTL0812 诱导内质网应激并阻断 Akt-mTOR 轴；这两个作用都集中在一起，激活了强大而持续的自噬，导致癌细胞死亡。临床前数据支持在癌症患者中开展临床试验。
这项首次人体试验包括一个递增阶段（3+3 设计），随后是一个扩展阶段，以评估 ABTL0812 的安全性和耐受性。次要目标是确定推荐的 II 期剂量（RP2D）、临床抗肿瘤活性、药代动力学（PK）和药效学（PD）。
共纳入 29 例患者并进行治疗；15 例患者在四个递增剂量组中接受治疗（剂量范围为每天一次 500mg 至每天两次 2000mg），14 例患者在扩展阶段接受治疗（每天三次 1300mg 剂量）。未达到最大耐受剂量，RP2D 通过 PK/PD 建模确定。大多数与药物相关的不良事件为胃肠道 1-2 级。发现药物水平与 pAkt/Akt 比值之间存在相关性。观察到 2 例长期（>1 年）疾病稳定的病例。
ABTL0812 安全且具有可接受的耐受性，允许长期口服给药。根据 PK/PD 建模确定的 RP2D 为每天三次 1300mg，观察到初步的抗肿瘤疗效。
NCT02201823。
