378P - Determination of recommended phase II dose of ABTL0812, a novel regulator of Akt/mTOR axis, by pharmacokinetic-pharmacodynamic modelling

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical Research
Basic Scientific Principles
Presenter Jose Alfon
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors J. Alfon1, L. Vidal2, L. Gaba2, I. Victoria2, M. Gil3, B. Laquente3, M. Brunet2, H. Colom4, J. Ramis5, H. Perez-Montoyo1, M. Cortal1, M. Gomez-Ferreria1, P. Muñoz1, T. Erazo6, J.M. Lizcano6, C. Domenech1, P. Gascon2
  • 1R&d, Ability Pharmaceuticals SL, 08290 - Cerdanyola/ES
  • 2Intherunit, Hospital Clinic y Provincial de Barcelona, 08036 - Barcelona/ES
  • 3Medical Oncology, Institut Català d'Oncologia Hospital Duran i Reynals, 08908 - Barcelona/ES
  • 4Faculty Of Pharmacy, Universitat de Barcelona, 08028 - Barcelona/ES
  • 5R&d, ADMEservices, 08035 - Barcelona/ES
  • 6Protein Kinases Laboratory, Universitat Autonoma de Barcelona, 08193 - Barcelona/ES



ABTL0812 is an anticancer agent in clinical development with a novel mechanism of action. It inhibits the Akt/mTOR axis after binding to PPARs and subsequent induction of TRIB3, a pseudokinase that acts as a negative regulator of Akt. Preclinical studies have shown high efficacy in different tumor types including NSCLC, endometrial cancer, pancreatic cancer and neuroblastoma. ABTL0812 exhibits, efficacy in resistant models and synergy with chemotherapy while maintaining extremely low toxicity.


A phase Ib clinical trial with a 3 + 3 escalation design and an expansion phase was performed in patients with advanced solid tumors. Safety and tolerability were the main objectives of the trial. ABTL0812 pharmacokinetics (PK) was determined and the ratio between phosphorylated Akt and total Akt (pAkt/Akt) levels in platelets was used as pharmacodynamic (PD) biomarker. Preliminary antitumor activity was evaluated by RECIST 1.1 criteria.


In the dose-escalation phase, 15 patients received 500 mg qd, 1000 mg qd, 1000 mg bid and 2000 mg bid. Other 14 patients were included in the expansion part at a dose of 1300 mg tid. No dose-limiting toxicities were detected. Most AEs were grade 1-2, and only one patient had drug-related grade 3-4 AEs. Several long-term disease stabilizations were observed, including one patient with cholangiocarcinoma (≥68 weeks), one with endometrial cancer (60 weeks) and three with colorectal cancer (22-28 weeks). Linear pharmacokinetics was described after multiple daily dosing, as well as dose-dependent inhibition of pAkt/Akt. A PK/PD Inhibitory Effect Emax model was performed and it was found that at least bid administration was required to have sustained inhibition of the biomarker >50%. In addition, it was shown that 1300 mg tid achieved pAkt/Akt inhibition in the range 74.7-95.5%, confirming that this dose induced the highest inhibition of the pathway.


Phase Ib clinical trial results have shown a high safety profile and signs of efficacy. PK has been described and concentration-dependent inhibition of a surrogate biomarker has been demonstrated. RP2D was established at 1300 mg tid based on a PK/PD analysis using the ratio of pAkt/Akt in platelets as a surrogate biomarker.

Clinical trial identification

Eudra CT 2013-001293-17; Clinicaltrials.gov NCT02201823

Legal entity responsible for the study

Hospital Clinic i Provincial de Barcelona Institut Català d'Oncologia


Ability Pharmaceuticals SL


J. Alfon, H. Perez-Montoyo, M. Cortal, M. Gomez-Ferreria: I am employee of ABTL0812, sponsor of the clinical trial. P. Muñoz: Employee of Ability Pharma. T. Erazo: Participates in a corporate-sponsored research. J.M. Lizcano, P. Gascon: Participates in a corporate-sponsored research Member of Advisory Board C. Domenech: I am employee of ABTL0812, sponsor of the clinical trial I hold stock ownership in Ability Pharma. All other authors have declared no conflicts of interest.