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%，是第三大致癌原因 死亡率。PAC的预后很差，几十年来几乎没有变化，表明 目前的治疗方法是不够的。因此，迫切需要新的疗法来治疗这种致命的疾病。 ABTL0812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PI3/Akt/mTor(PAM)通路，从而诱导 TRIB3，一种与Akt结合并阻碍其激活的假性激酶，导致mTOR抑制和 从而导致自噬依赖的癌细胞死亡。PAM途径与肿瘤的发生有关 许多癌症，包括PAC，以及对不同治疗方法的耐药性的形成，如 化疗。由于ABTL0812靶标在胰腺细胞中表达，因此ABTL0812在体外和在 在PAC模型中，作为单一药物显示抗肿瘤活性，并通过诱导联合化疗 一种增强效应。ABTL0812成功完成了首个人类I期临床试验(EudraCT 2013- 001293-17)，在那里它被证明是安全和耐受性的。建议的第二阶段 剂量(RP2D)是基于PK/PD模型确定的，因为没有检测到剂量限制毒性和 没有达到最大耐受量。此外，长达18个月的几次疾病稳定 都被发现了，表明了潜在的疗效迹象。这些有希望的结果导致了正在进行的I/II期临床 试验中，ABTL0812作为一线药物与紫杉醇和卡铂(P/C)联合应用 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。同样的方案得到了食品和药物管理局的批准(IND 137394)。到目前为止，第一阶段 第二阶段的中期成果显示了长期的反应。在欧共体的手臂上， ABTL0812与P/C结合可将P/C单独的效果提高近50%；ORR从52%提高到 75%。拟议的I/II期研究的目的是评估ABTL0812与吉西他滨和 NAB-紫杉醇(GM/P)作为转移性PAC的一线治疗方案基于PAM途径在细胞周期调控中的重要作用 PAC和化疗耐药，在我们的临床前数据中显示ABTL0812增强GM/P 疗效，加上临床数据，我们预计这项试验将证明ABTL0812改善了 PAC的临床治疗。此外，还将运行一个生物标记物程序，该程序可能会导致响应预测 伴随诊断。这项研究将是ABTL0812潜在临床应用的第一步。 善待政治行动委员会。一旦第一阶段部分完成，ABTL0812与GM/P相结合的安全性和耐受性 将会被确定。在随后的第二阶段，拟议综合治疗的疗效与 化疗将会确定。如果检测到显著改善，将导致更大的II期或 III试验证实本病患者S治疗有改善。

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.