A Phase 1 Clinical Trial Evaluating the Novel Small Molecule Immuno-Oncology Antagonist SX-682 Alone and With Pembrolizumab in Metastatic Melanoma
评估新型小分子免疫肿瘤拮抗剂 SX-682 单独使用以及与 Pembrolizumab 联合治疗转移性黑色素瘤的 1 期临床试验
基本信息
- 批准号:10189528
- 负责人:
- 金额:$ 65.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-04 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:Autocrine CommunicationB-LymphocytesBiopsyBlood CirculationCD4/CD8 ratio procedureCTLA4 geneCell AgingChemoresistanceClinicClinicalCorrelative StudyCyclic GMPDataData AnalyticsDisease ProgressionDisease remissionDistantDoseDose-LimitingExhibitsFDA approvedFormulationGenetically Engineered MouseGoalsGrowthHourHumanIL8 geneIL8RA geneIL8RB geneImmune checkpoint inhibitorImmune systemImmunologic MarkersImmunologic SurveillanceImmunooncologyImmunotherapyInterleukin 8A ReceptorLaboratoriesLigandsLymphocyteMalignant NeoplasmsMediatingMelanoma CellMetastatic MelanomaModelingMyeloid-derived suppressor cellsMyeloproliferative diseaseNeoplasm MetastasisNivolumabOncologyOralOrganOutcomePatient-Focused OutcomesPatientsPharmaceutical PreparationsPhasePhase I Clinical TrialsProgression-Free SurvivalsProtein IsoformsProtocols documentationPublishingRecordsRegulatory T-LymphocyteRestRoleSafetySignal TransductionSiteSolid NeoplasmT-LymphocyteTestingTherapeuticTherapeutic EffectToxic effectTumor BurdenTumor Cell InvasionUnited StatesUnited States National Institutes of HealthWorkangiogenesisanti-CTLA-4 therapyanti-CTLA4anti-PD-1anti-PD1 therapybasecell motilitycheckpoint inhibitionchemokinechemokine receptorchemotherapycostefficacy evaluationepithelial to mesenchymal transitionfightingfirst-in-humaninhibitor/antagonistipilimumabmelanomaneoplasm immunotherapyneoplastic cellneutrophilnovelopen labeloptimismpembrolizumabphase I trialpre-clinicalreceptorrecruitresearch clinical testingside effectsmall moleculestemnesssuccesstrial designtumortumor-immune system interactions
项目摘要
The chemokine receptors CXCR1 and CXCR2 (CXCR1/2) are validated as having essential roles in the
growth, survival, motility, invasion and angiogenesis of human melanoma, which secretes abundant amounts
of the corresponding chemokine ligands, including CXCL8. Additionally, abnormal cancer-induced
immunosuppressive myeloid-derived suppressor cells (MDSCs) in the circulation and tumor correlate with
melanoma stage, metastatic tumor burden, lack of progression-free survival and non-response to
immunotherapy. MDSCs potently suppress immune surveillance, promote tumor cell invasion, angiogenesis
and neutralize tumor cell senescence. MDSCs are recruited to tumors through activation of human chemokine
receptor isoforms CXCR1/2. Dual CXCR1/2 blockade is thus a validated therapeutic strategy to deliver a
multi-pronged attack on (i) melanoma cells that depend on CXCR1/2 autocrine signaling for growth, (ii)
CXCR1/2-driven angiogenesis and (iii) CXCR1/2-driven recruitment of MDSCs. SX-682 is a new-in-class oral,
small-molecule, immuno-oncology (IO) therapy directed at disrupting CXCR1/2 signaling. SX-682 has a
mechanism unlike any current IO agent, and unlike conventional chemotherapeutics, SX-682 is extremely well-
tolerated with no dose-limiting toxicity (DLT). SX-682 works via a novel intracellular site, and exhibits durable
antagonism of both receptors (> 12 hours). SX-682 exhibits significant activity in solid tumor models, where it
reversed chemoresistance, extended overall survival, and in syngeneic and genetically engineered mouse
(GEM) melanoma models, potently synergized with anti-PD1 therapy and caused complete remissions. Based
on these data and the preclinical mechanistic data published by many other independent laboratories, we
hypothesize that combining SX-682 with pembrolizumab in metastatic melanoma will afford enhanced efficacy
vs. historical pembrolizumab monotherapy, but with no added toxicity. If successful, SX-682 would be a critical
new addition to the existing treatment landscape in metastatic melanoma. Through execution of the Specific
Aims, we will advance SX-682 through critical first-in-man proof-of-concept (POC) testing in human melanoma
(the first ever of a CXCR1 or CXCR2 inhibitor). The open-label 3+3 escalation and expansion trial design is
standard for this POC testing in oncology. The primary objective is to determine the safety profile of SX-682
alone and with pembrolizumab. Secondary objectives are to evaluate SX-682 efficacy and characterize its
single-dose and multidose PK profile. Correlative studies will examine efficacy vs. immune biomarkers: tumor
MDSCs, Tregs and T cells (serial biopsies), and circulating MDSCs, neutrophils, neutrophil-to-lymphocyte ratio
(NLR), Tregs, T- and B-cells, the CD4:CD8 ratio. Based on preclinical data, we hypothesize SX-682 plus
pembrolizumab will exhibit enhanced efficacy vs. historical pembrolizumab efficacy, but without added toxicity.
If successful, this would be a major clinical advance in the treatment of metastatic melanoma.
趋化因子受体CXCR 1和CXCR 2(CXCR 1/2)被证实在免疫调节中具有重要作用。
人黑色素瘤的生长、存活、运动、侵袭和血管生成,其分泌大量
相应的趋化因子配体,包括CXCL 8。此外,异常的癌症诱导
循环和肿瘤中的免疫抑制性髓源性抑制细胞(MDSC)与
黑色素瘤分期、转移性肿瘤负荷、无进展生存期缺乏和对
免疫疗法。MDSC有效抑制免疫监视,促进肿瘤细胞侵袭,血管生成
中和肿瘤细胞衰老。MDSC通过激活人趋化因子被募集到肿瘤中
受体亚型CXCR 1/2。因此,双重CXCR 1/2阻断是一种有效的治疗策略,
对(i)依赖CXCR 1/2自分泌信号传导生长的黑素瘤细胞的多管齐下的攻击,(ii)
CXCR 1/2驱动的血管生成和(iii)CXCR 1/2驱动的MDSC募集。SX-682是一种新型的口腔,
小分子,免疫肿瘤学(IO)治疗,旨在破坏CXCR 1/2信号传导。SX-682具有
与目前任何IO剂不同的机制,也与传统的化疗药物不同,SX-682非常好-
耐受,无剂量限制性毒性(DLT)。SX-682通过一个新的细胞内位点发挥作用,并表现出耐用性
两种受体的拮抗作用(> 12小时)。SX-682在实体瘤模型中表现出显着的活性,其中它
逆转化疗耐药性,延长总生存期,并在同基因和基因工程小鼠中
(GEM)黑色素瘤模型,与抗PD 1治疗有效协同并引起完全缓解。基于
根据这些数据和许多其他独立实验室发表的临床前机制数据,我们
假设SX-682与帕博利珠单抗联合治疗转移性黑色素瘤将提高疗效
vs.历史上的派姆单抗单药治疗,但没有增加毒性。如果成功,SX-682将是一个关键的
转移性黑色素瘤现有治疗前景的新补充。通过执行具体的
目的是,我们将推进SX-682在人类黑色素瘤中通过关键的首次人体概念验证(POC)测试
(the首次使用CXCR 1或CXCR 2抑制剂)。开放标签3+3递增和扩展试验设计是
肿瘤学POC测试的标准。主要目的是确定SX-682的安全性
单独和与派姆单抗一起。次要目的是评价SX-682的疗效,并表征其
单次给药和多次给药PK特征。相关研究将检查疗效与免疫生物标志物:肿瘤
MDSC、TCF 4和T细胞(连续活检),以及循环MDSC、中性粒细胞、嗜中性粒细胞与淋巴细胞比率
(NLR)T细胞、T细胞和B细胞、CD 4:CD 8比值。基于临床前数据,我们假设SX-682加
派姆单抗将表现出与历史派姆单抗功效相比增强的功效,但没有增加的毒性。
如果成功,这将是转移性黑色素瘤治疗的一个重大临床进展。
项目成果
期刊论文数量(0)
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{{ truncateString('STUART J KAHN', 18)}}的其他基金
A Phase 1 Randomized Single Oral Dose Four Period Cross-Over Study Investigating Omnitram Dose Proportionality and Food Effect in Normal Human Subjects
一项 1 期随机单次口服剂量四期交叉研究,调查 Omnitram 剂量比例和食物对正常人类受试者的影响
- 批准号:
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- 资助金额:
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A Phase 1 Randomized Single Oral Dose Four Period Cross-Over Study Investigating Omnitram Dose Proportionality and Food Effect in Normal Human Subjects
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A Phase 1 Clinical Trial Evaluating the Novel Small Molecule Immuno-Oncology Antagonist SX-682 Alone and With Pembrolizumab in Metastatic Melanoma
评估新型小分子免疫肿瘤拮抗剂 SX-682 单独使用以及与 Pembrolizumab 联合治疗转移性黑色素瘤的 1 期临床试验
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A Phase 1 Clinical Trial Evaluating the Novel Small Molecule Immuno-Oncology Antagonist SX-682 Alone and With Pembrolizumab in Metastatic Melanoma
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