Phase I/II clinical evaluation of ABTL0812, a novel PI3K/Akt/mTOR inhibitor, with a unique mechanism of action inpancreatic cancer (Protocol sent on 20th June 2019 as an amendment of the IND 137394)

摘要

ABSTRACT Pancreatic Cancer (PaC) represents 3.2% of all new cancer cases in the US and is the third leading cause of cancer mortality. The prognosis for PaC is dismal and has remained almost unchanged for decades, indicating that current treatments are inadequate. Thus, there is an urgent need for new therapies for this mortal disease. ABTL0812 is a small molecule with anti-cancer activity through a unique mechanism of action. ABTL0812 inhibits the PI3/Akt/mTOR (PAM) pathway by binding to the nuclear receptors PPARα and γ, which induce TRIB3, a pseudo kinase that binds to Akt and impedes its activation, leading to mTOR inhibition and consequently to autophagy-dependent cancer cell death. The PAM pathway is responsible for the tumorigenesis of many cancers, including PaC, as well as for the development of resistance to different treatments, such as chemotherapy. Since ABTL0812 targets are expressed in pancreatic cells, ABTL0812 was tested in vitro and in vivo in PaC models, showing antitumor activity as a single agent and combined with chemotherapy by inducing a potentiation effect. ABTL0812 successfully concluded a First-in-Human Phase I clinical trial (EudraCT 2013- 001293-17) in advance solid tumors, where it was shown its safety and tolerability. The recommended Phase II dose (RP2D) was determined based on PK/PD modelling, since no Dose-Limiting Toxicities were detected and a Maximum Tolerated Dose was not achieved. Additionally, several long disease stabilizations of up to 18 months were found, indicating potential signs of efficacy. These promising results led to an ongoing Phase I/II clinical trial, where ABTL0812 is given as first line therapy in combination with paclitaxel and carboplatin (P/C) in patients with advanced endometrial cancer (EC) or squamous non-small cell lung carcinoma (EudraCT 2016- 001352-21) in Spain and France. The same protocol is approved by the FDA (IND 137394). To date, phase I has been successfully completed and interim results of the phase II has shown long-term responses. In the EC arm, ABTL0812 combined with P/C increases by almost 50% the efficacy of P/C alone; ORR is increased from 52% to 75%. The aim of the proposed phase I/II study is to evaluate ABTL0812 in combination with gemcitabine and nab-paclitaxel (Gm/P) as first line therapy in metastatic PaC. Based on the important role of PAM pathway in PaC and in chemotherapy resistance, and in our preclinical data that shows that ABTL0812 potentiates Gm/P efficacy, together with the clinical data, we expect that this trial will demonstrate that ABTL0812 improves the clinical treatment of PaC. In addition, a biomarkers program will be run that could lead to a response prediction companion diagnostic. This study will be the first step towards the potential clinical application of ABTL0812 to treat PaC. Once the phase I part is completed, the safety and tolerability of ABTL0812 in combination with Gm/P will be determined. In the subsequent phase II, the efficacy of the proposed combined treatment compared to chemotherapy will be determined. If a significant improvement is detected, that will lead to a larger phase II or III trial to confirm this patient´s treatment improvement.