HLS- A Phase 1 Open-Label Dose-Escalation with Expansion Study of SX-682 in MDS Patients

HLS-SX-682 在 MDS 患者中的 1 期开放标签剂量递增和扩展研究

• 批准号: 9789451
• 负责人: STUART J KAHN
• 金额: $ 142.44万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789451
• 关键词: Acute Myelocytic Leukemia; Affect; B-Lymphocytes; Biological Markers; Bone Marrow; Businesses; Cells; Clinic; Clinical; Clinical Data; Code; Cooperative Research and Development Agreement; Cyclic GMP; Data Analytics; Dependence; Disease; Disease remission; Dose; Dose-Limiting; Dysmyelopoietic Syndromes; Enrollment; Evaluation; Exhibits; FDA approved; Failure; Formulation; Funding; Goals; Growth; Hematological Disease; Hematology; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; IL8 gene; IL8RA gene; IL8RB gene; Immunologic Surveillance; Immunooncology; Immunosuppressive Agents; Immunotherapeutic agent; Impairment; Lead; Life; Ligands; Marrow; Measures; Metastatic Melanoma; Morphology; Myeloid-derived suppressor cells; National Heart, Lung, and Blood Institute; Natural Killer Cells; Non-Malignant; Oral; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Prior Therapy; Protocols documentation; Records; Refractory; Regulatory T-Lymphocyte; Relapse; Risk; Safety; Severities; Signal Transduction; Site; Small Business Innovation Research Grant; Somatic Mutation; Stem cells; Symptoms; Syndrome; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transfusion; United States; Work; acute myeloid leukemia cell; base; blood product; cell growth; chemokine; cohort; cost; cytopenia; gene therapy; granulocyte-monocyte progenitors; high risk; immune clearance; interest; melanoma; mutant; neutrophil; novel; novel therapeutics; open label; outcome forecast; overexpression; pre-clinical; progenitor; receptor; recruit; research clinical testing; response; side effect; small molecule; standard of care; stem; therapeutic target

This SBIR Fast-Track proposal meets the objectives of NHLBI Small Business Topic of Special Interest for Fiscal Year 2017 Code HLS17-04. Myelodysplastic syndromes (MDS) are genetically and morphologically diverse hematopoietic neoplasms that arise from a small pool of mutant clones within hematopoietic stem and progenitor compartments. Only three drugs have received regulatory approval specifically for MDS treatment, all with suboptimal response rates of <50% and of limited durability, typically 1-2 years. Once these agents are no longer effective, there is no standard of care established for second-line treatment (i.e., in the relapsed/refractory setting). Furthermore, prognosis after hypomethylating agent failure is dismal, with median survival estimated at <6 months for higher-risk patients, and <18 months for lower-risk patients. Clearly there is a significant unmet need for a new MDS treatment that both (a) eradicates preleukemic stem cells and leads to long-term remission and normalization of cytopenias, and (b) achieves this goal without the heavy cost of side effects, particularly in lower-risk MDS. Stem cells and early progenitors from MDS patients consistently overexpressed the chemokine CXCL8 (IL-8) and its receptor, CXCR2. Inhibition of CXCR2 selectively arrested the growth of stem cells from MDS patients but not healthy controls, demonstrating preclinical therapeutic proof-of-principle and validating CXCR2 as a therapeutic target in MDS. Additionally, myeloid-derived suppressor cells (MDSCs) are markedly increased in the bone marrow of MDS patients where they induce myelodysplasia and impair immune surveillance and clearance of mutant clones. CXCR2 and CXCR1 are pivotal in MDSC recruitment. Dual CXCR1 and CXCR2 (CXCR1/2) inhibition is therefore a novel therapeutic strategy to treat MDS with a “one- two punch” to (i) the mutant MDS cells directly and (ii) the MDSC-driven immunosuppressive marrow microenvironment. Developed by Syntrix in a decade's long discovery effort supported by NHLBI (IND open for melanoma 4/16), SX-682 is a new-in-class oral, small-molecule, immuno-oncology (IO) therapy directed at disrupting CXCR1/2 signaling. We hypothesize that in MDS, SX-682 will lead to long-term remissions and normalization of cytopenias, but with only a mild side-effect effect profile compared to other therapies. If successful, SX-682 would revolutionize the existing treatment landscape in MDS. Through execution of the Specific Aims, we will advance SX-682 through a Phase 1, open label dose-escalation and expansion trial to evaluate SX-682 in MDS patients who had progression or were intolerant to prior therapy. The SX-682 MDS IND 131,876 was opened on September 1, 2017, and enrollment for this trial may begin.

此 SBIR 快速通道提案符合 NHLBI 小企业特别感兴趣主题的目标 2017 财年代码 HLS17-04。骨髓增生异常综合征 (MDS) 具有遗传和形态学特征 由造血干细胞内的一小部分突变克隆产生的多种造血肿瘤 祖室。只有三种专门用于MDS治疗的药物获得了监管部门的批准， 所有这些的响应率都低于 50%，且持续时间有限，通常为 1-2 年。一旦这些代理 不再有效，没有为二线治疗制定护理标准（即在 复发/难治性情况）。此外，低甲基化药物失败后的预后很差，中位 高风险患者的生存估计为<6个月，低风险患者的生存估计为<18个月。显然有 对于一种新的 MDS 治疗方法来说，这是一个未得到满足的重大需求，该治疗方法既可以 (a) 根除白血病前期干细胞，又可以导致 血细胞减少症的长期缓解和正常化，并且（b）无需付出高昂的代价即可实现这一目标 副作用，特别是在低风险 MDS 中。 MDS 患者的干细胞和早期祖细胞始终过度表达趋化因子 CXCL8 (IL-8) 及其受体 CXCR2。抑制 CXCR2 可选择性抑制 MDS 干细胞的生长 患者而非健康对照，展示临床前治疗原理验证并验证 CXCR2 作为 MDS 的治疗靶点。此外，骨髓源性抑制细胞 (MDSC) 显着 MDS 患者的骨髓增加，导致骨髓增生异常并损害免疫系统 突变克隆的监视和清除。 CXCR2 和 CXCR1 在 MDSC 招募中至关重要。双重的 因此，CXCR1 和 CXCR2 (CXCR1/2) 抑制是一种新的治疗策略，以“单- “两拳”直接作用于（i）突变型 MDS 细胞和（ii）MDSC 驱动的免疫抑制骨髓 微环境。 由 Syntrix 在 NHLBI 支持下经过十年的长期发现努力而开发（针对黑色素瘤的 IND 开放） 4/16)，SX-682 是一种新型口服小分子免疫肿瘤 (IO) 疗法，旨在破坏 CXCR1/2 信号传导。我们假设在 MDS 中，SX-682 将导致长期缓解和正常化 血细胞减少症，但与其他疗法相比只有轻微的副作用。如果成功，SX-682 将彻底改变 MDS 现有的治疗格局。通过具体目标的执行，我们将 通过第一阶段、开放标签剂量递增和扩展试验推进 SX-682，以评估 SX-682 病情进展或对先前治疗不耐受的 MDS 患者。 SX-682 MDS IND 131,876 是 于 2017 年 9 月 1 日开放，该试验的注册可能会开始。