A first-in-human phase I/Ib dose-escalation clinical trial of the autophagy inducer ABTL0812 in patients with advanced solid tumours.

Abstract

BACKGROUND\nABTL0812 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.\n\n\nPATIENTS AND METHODS\nThis first-in-human trial consisted of an escalation phase (3\xa0+\xa03 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).\n\n\nRESULTS\nA total of 29 patients were enrolled and treated; fifteen patients were treated in four escalation dosing cohorts (ranging from 500\xa0mg once a day to 2000\xa0mg twice a day) and fourteen in the expansion phase (dosed with 1300\xa0mg 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.\n\n\nCONCLUSIONS\nABTL0812 is safe and has an acceptable tolerability profile, allowing a long-term oral dosing. RP2D of 1300\xa0mg three times a day was determined according to PK/PD modelling, and preliminary antitumour efficacy was observed.\n\n\nCLINICAL TRIAL REGISTRATION NUMBER\nNCT02201823.