7HP349, an Integrin Activator to Treat Patients With anti-PD-1 Resistant Solid Tumors

项目总结/摘要 免疫肿瘤学（IO）疗法，特别是免疫检查点抑制剂（ICI），如纳武单抗（抗PD-1）。 1)和易普利姆玛（抗CTLA-4）在诱导患者显著应答率方面取得了快速进展， 在各种实体瘤中。然而，超过40%的黑色素瘤患者会对aPD-1产生继发性耐药 基础治疗，治疗选择有限。 整合素α4β1和αLβ2对抗原呈递、T细胞引发和运输至关重要。7 HP 349是一种口服 α4β1和αLβ2整联蛋白的变构激动剂，可能逆转抗PD-1耐药性并增加ICI 在这些患者中有效，而不增加毒性。7 HP 349在体外显示增强的T细胞活性，并且 在肿瘤模型中增强的抗肿瘤功效和存活率，增加T细胞浸润到肿瘤中，但不 正常组织。我们在7 HP 349的开发方面取得了重大进展，包括批准孤儿 黑色素瘤的药物认定（ODD）和快速通道认定，并完成首次人体试验（FIH） 7 HP 349的安全性、耐受性和药代动力学的I期研究，以及最佳药代动力学剂量 (OPD)定义为Ib/IIa期。 我们的假设是，用伊匹单抗的标准方案增强T细胞应答， 与7 HP 349联合，然后是纳武单抗单一疗法的维持方案将改善 在具有继发性aPD-1耐药性的实体瘤患者中，在这里我们提出了一个 使用7 HP 349进行的Ib期剂量递增研究（7 HP-111 a），旨在评价7 HP 349在以下患者中的安全性、耐受性和PK： 在实体瘤患者中与伊匹单抗组合，然后依次进行纳武单抗单药治疗 （黑色素瘤，胸膜间皮瘤，肾细胞癌，MSI高或错配修复缺陷的结肠直肠癌， 无EGFR或间变性淋巴瘤激酶（ALK）的肝细胞癌和非小细胞肺癌 基因组肿瘤畸变），具有继发性aPD-1抗性。T细胞活化研究也将在 对患者样品进行，并收集活检作为本研究的一部分。拟定的Ib期研究将不会 仅允许后续设计和进行未来IIa期剂量扩展研究，以评估 7 HP 349与伊匹单抗组合随后是纳武单抗单一疗法的初步功效 在对aPD-1治疗继发性耐药的黑色素瘤患者中， 这类患者的治疗选择。

PROJECT SUMMARY/ABSTRACT Immuno-oncology (IO) therapies, particularly immune checkpoint inhibitors (ICIs) such as nivolumab (anti-PD- 1) and ipilimumab (anti-CTLA-4) have made rapid advances in inducing remarkable response rates in patients in a variety of solid tumors. However, over 40% of melanoma patients develop secondary resistance to aPD-1- based therapy, and have limited treatment options. Integrins α4β1 and αLβ2 are crucial for antigen presentation, T cell priming and trafficking. 7HP349 is an oral allosteric agonist of α4β1 and αLβ2 integrins, that may potentially reverse anti-PD-1 resistance and increase ICI effectiveness in these patients, without elevating toxicity. 7HP349 shows augmented T cell activity in vitro, and enhanced antitumor efficacy and survival in tumor models, with increased T cell infiltration into tumors but not to normal tissues. We have made significant progress with 7HP349 development, including approval of Orphan Drug Designation (ODD) and Fast-Track Designation for melanoma, and completion of a first-in-human (FIH) Phase I study of the safety, tolerability and pharmacokinetics of 7HP349, with the optimal pharmacokinetic dose (OPD) defined for Phase Ib/IIa. Our hypothesis is that the augmentation of T cell responses with a standard regimen of ipilimumab in combination with 7HP349, followed by a maintenance regimen of nivolumab monotherapy will improve responses without added toxicity in solid tumor patients with secondary aPD-1 resistance. Here we propose a Phase Ib dose escalation study (7HP-111a) with 7HP349 to evaluate the safety, tolerability and PK of 7HP349 in combination with ipilimumab followed sequentially by nivolumab monotherapy in solid tumor patients (melanoma, pleural mesothelioma, renal cell carcinoma, MSI-high or mismatch repair-deficient colorectal cancer, hepatocellular carcinoma, and non-small cell lung cancer with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations) who have secondary aPD-1 resistance. T cell activation studies will also be performed on patient samples, and biopsies collected as part of this study. The proposed Phase Ib study will not only enable the subsequent design and conduct of a future Phase IIa dose expansion study to evaluate the preliminary efficacy of 7HP349 in combination with ipilimumab followed sequentially by nivolumab monotherapy in melanoma patients with secondary resistance to aPD-1 therapy, but potentially lay the foundation for novel treatment options in such patients.