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

基本信息

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
项目类别：
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

项目摘要

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.

该SBIR快速轨道提案符合NHLBI小型商业主题的特殊兴趣的目标 2017财年代码HLS17-04。骨髓增生综合征（MD）在遗传和形态上是潜水的造血性肿瘤，是由造血茎中的一小群突变克隆引起的祖先室。只有三种药物已获得专门用于MDS治疗的法规批准，所有次优响应率<50％且耐用性有限，通常为1 - 2年。一旦这些代理人不再有效，没有确定二线治疗的护理标准（即复发/难治设置）。此外，低甲基化剂衰竭后的预后是令人沮丧的，中位数高危患者估计的生存率<6个月，低危患者<18个月。显然在那里是对新的MDS处理的重要需求长期缓解和细胞质的归一化，（b）实现此目标，而无需高昂的成本副作用，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表达趋化因子CXCL8 （IL-8）及其接收器CXCR2。 CXCR2的抑制选择性阻止了MDS干细胞的生长患者但不是健康的对照，证明了临床前治疗证明和验证CXCR2 作为MDS中的治疗靶标。另外，髓样衍生的抑制细胞（MDSC）明显在MDS患者的骨髓中增加，它们诱导骨髓增生并损害免疫突变克隆的监视和清除率。 CXCR2和CXCR1在MDSC募集中是关键的。双重的因此，CXCR1和CXCR2（CXCR1/2）抑制是一种新型的治疗策略两次打孔到（i）直接的突变体MDS细胞和（ii）MDSC驱动的免疫抑制骨髓微环境。由Syntrix在NHLBI支持的十年中开发的长期发现（IND开放式黑色素瘤 4/16），SX-682是一种新的口服，小分子，免疫肿瘤（IO）治疗，旨在破坏 CXCR1/2信号传导。我们假设在MDS中，SX-682将导致长期恢复和归一化细胞质量，但与其他疗法相比仅具有轻度的副作用效果。如果成功，SX-682 将彻底改变MDS中现有的治疗环境。通过执行特定目标，我们将通过第1阶段的开放标签剂量升级和扩展试验提高SX-682，以评估SX-682 MDS患者的进展或不容忍先前治疗。 SX-682 MDS IND 131,876是于2017年9月1日开放，该试验的入学人数可能开始。