@article{6e76fd48c885495696e8d5bc2a0a4dba,
title = "A first-in-human phase I/Ib dose-escalation clinical trial of the autophagy inducer ABTL0812 in patients with advanced solid tumours",
abstract = "Background: 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. Patients and methods: 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). Results: 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. Conclusions: 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. Clinical trial registration number: NCT02201823.",
keywords = "ABTL0812, Akt, Autophagy, Cancer, ER stress, First-in-human, TRIB3, mTOR",
author = "Laura Vidal and Ivan Victoria and Lydia Gaba and Mart{\'i}n, {Marta Gil} and Merc{\`e} Brunet and Helena Colom and Marc Cortal and Mariana G{\'o}mez-Ferrer{\'i}a and Marc Yeste-Velasco and Antonio Perez and Jordi Rodon and Sohal, {Davendra P.S.} and Lizcano, {Jos{\'e} Miguel} and Carles Dom{\`e}nech and Jos{\'e} Alf{\'o}n and Pere Gasc{\'o}n",
note = "Funding Information: The authors acknowledge the assistance of Clara Fermoselle and Carles Morte (Kymos Pharma Services) in the development and analysis of biomarkers and Joaquim Ramis (ADME Services) for the PK/PD analysis. This work was sponsored by Ability Pharmaceuticals SL and supported by the Spanish Ministerio de Econom{\'i}a y Empresa (MINECO) [grant numbers PID/IDI-20101630, IPT-2012-0614-010000, RTC-2014-1532-1, RTC-2014-2589-1, INNOCASH/2011196, EBT2012/100375, INC-TU-2012-2617 to M.C., PTQ-11-04.900 to J.A. and PTQ-12-05.453 to MGF], and Government of Generalitat of Catalonia [FINEBT 10-1-0047]. Funding Information: The authors acknowledge the assistance of Clara Fermoselle and Carles Morte (Kymos Pharma Services) in the development and analysis of biomarkers and Joaquim Ramis (ADME Services) for the PK/PD analysis. This work was sponsored by Ability Pharmaceuticals SL and supported by the Spanish Ministerio de Econom?a y Empresa (MINECO) [grant numbers PID/IDI-20101630, IPT-2012-0614-010000, RTC-2014-1532-1, RTC-2014-2589-1, INNOCASH/2011196, EBT2012/100375, INC-TU-2012-2617 to M.C. PTQ-11-04.900 to J.A. and PTQ-12-05.453 to MGF], and Government of Generalitat of Catalonia [FINEBT 10-1-0047]. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2021",
month = mar,
doi = "10.1016/j.ejca.2020.12.019",
language = "English (US)",
volume = "146",
pages = "87--94",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier Limited",
}