Abstract LB-C18: First-in-Human Clinical Trial of ABTL0812, a Compound that Inhibits PI3K/Akt/mTOR Pathway by Upregulating TRIB3, in Patients with Advanced Solid Tumors
Authors: Vidal Laura , Gaba Lydia , Victoria Ivan , Gil-Martin Marta , Laquente Berta , Cortal Marc , Brunet Merce , Paredes Pilar , Gomez-Ferreria Mariana , Alfon Jose , Domenech Carles , Gascon Pedro 
Published: May 2016

Abstract
Background: ABTL0812 is a first-in-class antitumor drug whose mechanism of action relies on the inhibition of PI3K/Akt/mTOR (PAM) pathway by upregulation of TRIB3 levels, an endogenous inhibitor of Akt activity that prevents Akt phosphorylation. Preclinical studies showed good efficacy of ABTL0812 in xenograft models with high safety margin. Here we describe the First-in-Human (FiH) Phase I/Ib clinical trial of ABTL0812 in patients with advanced solid tumors (NCT02201823).
Methods: ABTL0812 was dosed daily, by the oral route, in 28-day cycles. The study included a 4-cohort dose escalation, in a 3+3 dose escalating design, followed by an expansion cohort. The trial objectives were to determine safety and tolerability, to evaluate signs of efficacy, to determine drug pharmacokinetics (PK) in plasma and to analyze inhibition of Akt phosphorylation in platelets by MSD® as pharmacodynamic (PD) biomarker. Pretreatment tumor biopsies were analyzed by next generation sequencing to identify mutations in a panel of 50 cancer-related genes.
Results: Fifteen patients were recruited in the escalation part and 14 patients in the expansion cohort (February 2014 to May 2015). No dose-limiting-toxicities were detected and the recommended Phase II was 1300 mg tid based on PK/PD modeling. The median number of previous chemotherapy lines was 2 (range 0-11). The profile of ABTL0812 grade 1-2 related adverse events (AEs) included asthenia, nausea/vomiting and throat burning (34%, 31% and 24% of patients, respectively). Only one case of grade 3-4 AE (elevated hepatic enzymes) appeared. ABTL0812 half-life was short (3-5 h), which supported the increase in the administration schedule from once to twice and finally to three times a day. Biomarker analysis showed inhibition of Akt phosphorylation with increasing doses, with average 90% inhibition in the expansion cohort; furthermore it correlated with C-trough plasma levels. Five patients had stable disease (SD) for at least 16 weeks: 1 endometrial cancer (62 weeks), 1 cholangiocarcinoma (35 weeks, ongoing on Sep 15th, 2015), 2 colorectal cancer (28 and 22 weeks) and 1 lung adenocarcinoma (16 weeks). The median time to progression in the expansion cohort was 11 weeks (range 1-≥35 weeks). Interestingly, the tumor biopsy from the patient with endometrial cancer had activating mutations in Akt1 (E17K) and PIK3CA (R88Q). The tumor from the patient with colorectal cancer (28 weeks SD) showed deleterious mutations in TP53 (R248W) and APC (Q1469Ter). None of these samples included major mutations in Ras.
Conclusions: ABTL0812 is a PAM pathway inhibitor acting by a novel mechanism of action that involves upregulation of TRIB3 levels. The FiH Phase I/Ib study in patients with advanced solid tumors showed excellent tolerability and safety profile and demonstrated dose-dependent inhibition of Akt phosphorylation. ABTL0812 treatment induced several long term disease stabilizations (5/29), being the best responder a patient with endometrial cancer (68 weeks) with activating mutations in Akt1 and PIK3CA. Based on these data, a Phase II clinical trial in patients with endometrial cancer is planned.
Citation Format: Laura Vidal, Lydia Gaba, Ivan Victoria, Marta Gil-Martin, Berta Laquente, Marc Cortal, Merce Brunet, Pilar Paredes, Mariana Gomez-Ferreria, Jose Alfon, Carles Domenech, Pedro Gascon. First-in-Human Clinical Trial of ABTL0812, a Compound that Inhibits PI3K/Akt/mTOR Pathway by Upregulating TRIB3, in Patients with Advanced Solid Tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C18.