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 胰腺癌（PaC）占美国所有新发癌症病例的3.2%，是第三大癌症原因 mortality. PaC的预后很差，几十年来几乎没有变化，这表明， 目前的治疗是不够的。因此，迫切需要针对这种致命疾病的新疗法。 ABTL 0812是一种通过独特的作用机制具有抗癌活性的小分子。ABTL0812 通过与核受体PPARα和γ结合抑制PI 3/Akt/mTOR（PAM）通路， Trib 3是一种假激酶，与Akt结合并阻碍其激活，导致mTOR抑制， 从而导致自噬依赖性癌细胞死亡。PAM通路负责肿瘤的发生 许多癌症，包括PaC，以及对不同治疗的耐药性，如 化疗由于ABTL 0812靶标在胰腺细胞中表达，因此在体外和体内测试ABTL 0812。 在PaC模型中，作为单一药剂和与化疗联合，通过诱导 增强效应。ABTL 0812成功完成首次人体I期临床试验（EudraCT 2013- 001293-17）在晚期实体瘤中的应用，其中显示了其安全性和耐受性。II期推荐 基于PK/PD建模确定剂量（RP 2D），因为未检测到剂量限制性毒性， a未达到最大耐受剂量。此外，几个长达18个月的长期疾病稳定期 这表明了潜在的功效迹象。这些有希望的结果导致了正在进行的I/II期临床试验。 试验，其中ABTL 0812作为一线治疗与紫杉醇和卡铂（P/C）联合给药， 晚期子宫内膜癌（EC）或鳞状非小细胞肺癌患者（EudraCT 2016- 001352-21）在西班牙和法国。FDA批准了相同的方案（IND 137394）。迄今为止，第一阶段已 第二阶段的中期结果显示了长期的反应。在EC组中， ABTL 0812联合P/C使单独P/C的疗效增加了近50%; ORR从52%增加到 百分之七十五所提议的I/II期研究的目的是评估ABTL 0812与吉西他滨的组合， 白蛋白结合型紫杉醇（Gm/P）作为转移性PaC的一线治疗。基于PAM途径在 我们的临床前数据显示ABTL 0812增强了Gm/P， 结合临床数据，我们预计该试验将证明ABTL 0812改善了 PaC的临床治疗此外，将运行一个生物标志物程序，该程序可能导致响应预测 伴随诊断。本研究将是ABTL 0812潜在临床应用的第一步， 治疗PaC。一旦I期部分完成，ABTL 0812与Gm/P组合的安全性和耐受性将被评估。 将被确定。在随后的II期研究中，将拟定的联合治疗与 化疗将被确定。如果发现有重大改进，将导致更大规模的第二阶段或第三阶段。 III试验，以确认该患者的治疗改善。

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.