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

7HP349，一种整合素激活剂，用于治疗抗 PD-1 耐药实体瘤患者

• 批准号: 10761171
• 负责人: LIONEL David LEWIS
• 金额: $ 99.92万
• 依托单位: 7 HILLS PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761171
• 关键词: Adverse event; Agonist; Antigen Presentation; Binding; Biopsy; Capital; Clinical Research; Colorectal Cancer; Complement; Consensus; Development; Dose; Dose Limiting; Drug Kinetics; Effectiveness; Epidermal Growth Factor Receptor; Food; Foundations; Funding; Future; Genomics; Goals; Immune checkpoint inhibitor; Immunooncology; In Vitro; In complete remission; Integrin alpha4beta1; Integrins; Maintenance; Malignant neoplasm of lung; Mediating; Medical; Metastatic Melanoma; Mismatch Repair Deficiency; Modeling; Nivolumab; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oral; Orphan Drugs; Overdose; Patients; Phase; Pleural Mesothelioma; Primary carcinoma of the liver cells; Privatization; Progressive Disease; Recommendation; Regimen; Renal Cell Carcinoma; Resistance; Safety; Sampling; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Solid Neoplasm; Stable Disease; T cell infiltration; T cell response; T-Cell Activation; T-Lymphocyte; Toxic effect; anaplastic lymphoma kinase; anti-CTLA4; anti-PD-1; anti-PD1 therapy; autoimmune toxicity; checkpoint therapy; design; first-in-human; immune checkpoint blockade; immunotoxicity; improved; in vitro activity; ipilimumab; melanoma; migration; novel; objective response rate; partial response; pembrolizumab; pharmacologic; phase 1 study; response; risk mitigation; safety study; standard of care; trafficking; tumor

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.

项目摘要/摘要 免疫肿瘤学（IO）疗法，特别是免疫抑制剂（ICIS），例如Nivolumab（抗PD- 1）和ipilimumab（抗CTLA-4）在患者的诱发反应率方面取得了迅速的进步 在各种实体瘤中。然而，超过40％的黑色素瘤患者对APD-1-- 基于治疗的治疗方法有限。 整联蛋白α4β1和αLβ2对于抗原表现，T细胞启动和运输至关重要。 7HP349是口头 α4β1和αLβ2整合素的变构激动剂，可能会逆转抗PD-1耐药性并增加ICI 这些患者的有效性，而无需升高毒性。 7HP349显示体外T细胞活性增强，并且 在肿瘤模型中提高了抗肿瘤效率和存活，T细胞浸润增加了肿瘤，但没有增加 到正常组织。我们在7HP349开发方面取得了重大进展，包括批准孤儿 黑色素瘤的药物名称（奇数）和快速轨道名称，并完成了第一人类（FIH） 第一阶段研究7HP349的安全性，耐受性和药代动力学，最佳药代动力学剂量 （OPD）定义为IB/IIA期。 我们的假设是用ipilimumab的标准方案在中的T细胞反应增强 与7HP349的结合，然后是Nivolumab单药治疗的维护方案 在具有继发性APD-1耐药性的实体瘤患者中没有毒性的反应。在这里我们提出一个 IB期剂量升级研究（7HP-111A）具有7HP349，以评估7HP349的安全性，耐受性和PK 与ipilimumab结合结合，然后在实体瘤患者中依次与nivolumab单药治疗 （黑色素瘤，胸膜间皮瘤，肾细胞癌，MSI-HIGH或不匹配修复缺陷的结直肠癌， 肝细胞癌和非EGFR或肿瘤淋巴瘤激酶（ALK）的非小细胞肺癌（ALK） 具有继发APD-1抗性的基因组肿瘤畸变。 T细胞激活研究也将是 在患者样品中进行，并作为本研究的一部分收集了活检。拟议的IB研究不会 仅允许将来的IIA剂量扩展研究的随后设计和执行以评估 7HP349与ipilimumab结合的初步效率，然后依次进行Nivolumab单一疗法 在黑色素瘤患者中对APD-1治疗的耐药性，但有可能为新颖的基础 此类患者的治疗选择。