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.

项目概要/摘要 免疫肿瘤学 (IO) 疗法，特别是免疫检查点抑制剂 (ICIs)，例如纳武单抗（抗 PD- 1) 和 ipilimumab（抗 CTLA-4）在诱导患者显着缓解率方面取得了快速进展 适用于多种实体瘤。然而，超过 40% 的黑色素瘤患者对 aPD-1 产生继发性耐药性 基础治疗，并且治疗选择有限。 整合素 α4β1 和 αLβ2 对于抗原呈递、T 细胞启动和运输至关重要。 7HP349是一种口服 α4β1 和 αLβ2 整合素的变构激动剂，可能逆转抗 PD-1 耐药性并增加 ICI 对这些患者有效，且不会增加毒性。 7HP349 显示体外 T 细胞活性增强，并且 增强肿瘤模型中的抗肿瘤功效和存活率，增加 T 细胞浸润到肿瘤中，但不增加 对正常组织。我们在 7HP349 开发方面取得了重大进展，包括孤儿药的批准 黑色素瘤药物指定 (ODD) 和快速通道指定，并完成首次人体试验 (FIH) 7HP349的安全性、耐受性和药代动力学I期研究，最佳药代动力学剂量 (OPD) 为 Ib/IIa 期定义。 我们的假设是，使用伊匹单抗标准方案可增强 T 细胞反应 与 7HP349 联合，随后采用纳武单抗单药维持方案将改善 对具有继发性 aPD-1 耐药性的实体瘤患者产生反应，且不会增加毒性。在这里我们提出一个 使用 7HP349 进行 Ib 期剂量递增研究 (7HP-111a)，以评估 7HP349 的安全性、耐受性和 PK 在实体瘤患者中与易普利姆玛 (ipilimumab) 联合治疗，随后序贯纳武单抗 (nivolumab) 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直肠癌、 肝细胞癌和无 EGFR 或间变性淋巴瘤激酶 (ALK) 的非小细胞肺癌 基因组肿瘤畸变）具有继发性 aPD-1 耐药性。 T细胞激活研究也将 对作为本研究一部分收集的患者样本和活检进行了分析。拟议的 Ib 期研究不会 仅允许后续设计和进行未来的 IIa 期剂量扩展研究以评估 7HP349 联合易普利姆玛 (ipilimumab) 联合纳武单抗 (nivolumab) 单药治疗的初步疗效 治疗对 aPD-1 治疗继发耐药的黑色素瘤患者，但可能为新的治疗奠定基础 此类患者的治疗选择。