A Phase I Study of INCB053914 (Pan-PIM Kinase Inhibitor) and Pomalidomide With Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

This is a prospective, single-center, open-label phase Ib study aimed at determining a recommended phase II dose of INCB053914 and pomalidomide with dexamethasone. The trial will follow a 3 + 3 phase I dose-escalation design.

开始日期2021-07-01

申办/合作机构

Medical College of Wisconsin

NCT03688152 / Completed临床1期

A Phase 1b, Multicenter, Open-Label Study of the Safety and Tolerability of INCB053914 in Combination With INCB050465 in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

The purpose of this study is to evaluate the safety and tolerability of INCB053914 in combination with INCB050465 in relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

开始日期2018-12-03

申办/合作机构

Incyte Corp.

NCT02587598 / Terminated临床1/2期

A Phase 1/2 Study of INCB053914 in Subjects With Advanced Malignancies

This is an open-label, dose-escalation study of the proviral integration site of Moloney murine leukemia virus (PIM) kinase inhibitor INCB053914 in subjects with advanced malignancies. The study will be conducted in 4 parts. Part 1 (monotherapy dose escalation) will evaluate safety and determine the maximum tolerated dose of INCB053914 monotherapy and the recommended phase 2 dose(s) (a tolerated pharmacologically active dose that will be taken forward into the remaining parts of the study). Part 2 (monotherapy dose expansion) will further evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the recommended Phase 2 dose(s). Part 3 (combination dose finding) will evaluate safety of INCB053914 in combination with select standard of care (SOC) agents and will identify the optimal INCB053914 dose in combination with conventional SOC regimens to take forward into Part 4. Part 4 (combination dose expansion) will further evaluate the safety, efficacy and pharmacokinetics of the recommended Phase 2 dose combination(s).

开始日期2015-12-29

申办/合作机构

Incyte Corp.

100 项与 Uzansertib 相关的临床结果

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100 项与 Uzansertib 相关的转化医学

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100 项与 Uzansertib 相关的专利（医药）

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项与 Uzansertib 相关的文献（医药）

2023-09-01·Clinical lymphoma, myeloma & leukemia

Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies.

Article

作者: Savona, Michael R ; Asch, Adam S ; Patel, Manish R ; Walker, Chris ; Cheng, Lulu ; Byrne, Michael ; Fathi, Amir T ; Kuykendall, Andrew T ; Baer, Maria R ; Donnellan, William ; Zeidan, Amer M ; Marando, Cindy ; Zheng, Fred

BACKGROUND:

The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are implicated in tumorigenesis; the pan-PIM kinase inhibitor, INCB053914, demonstrated antitumor activity in hematologic malignancy preclinical models.

PATIENTS AND METHODS:

This phase 1/2 study evaluated oral INCB053914 alone or combined with standard-of-care agents for advanced hematologic malignancies (NCT02587598). In Parts 1/2 (monotherapy), patients (≥18 years) had acute leukemia, high-risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm, myelofibrosis (MF), multiple myeloma, or lymphoproliferative neoplasms. In Parts 3/4 (combination therapy), patients had relapsed/refractory or newly diagnosed (≥65 years, unfit for intensive chemotherapy) acute myeloid leukemia (AML) or MF with suboptimal ruxolitinib response.

RESULTS:

Parts 1/2 (n = 58): 6 patients experienced dose-limiting toxicities (DLTs), most commonly aspartate aminotransferase/alanine aminotransferase-elevated (AST/ALT; each n = 4). Fifty-seven patients (98.3%) had treatment-emergent adverse events (TEAEs), most commonly ALT-elevated and fatigue (36.2% each); 48 (82.8%) had grade ≥3 TEAEs, most commonly anemia (31.0%); 8 (13.8%) had grade ≥3 ALT/AST-elevated TEAEs. Parts 3/4 (n = 39): for INCB053914 + cytarabine (AML; n = 6), 2 patients experienced DLTs (grade 3 maculopapular rash, n = 1; grade 3 ALT-elevated and grade 4 hypophosphatemia, n = 1); for INCB053914 + azacitidine (AML; n = 16), 1 patient experienced a DLT (grade 3 maculopapular rash). Two complete responses were observed (1 with incomplete count recovery). For INCB053914 + ruxolitinib (MF; n = 17), no DLTs occurred; 3 patients achieved best reduction of >25% spleen volume at week 12 or 24.

CONCLUSION:

INCB053914 was generally well tolerated as monotherapy and in combinations; TEAEs were most commonly ALT/AST-elevated. Limited responses were observed with combinations. Future studies are needed to identify rational, effective combination strategies.

2020-04-01·Fish & shellfish immunology2区 · 农林科学

RNA-Seq analysis reveals that spring viraemia of carp virus induces a broad spectrum of PIM kinases in zebrafish kidney that promote viral entry

2区 · 农林科学

Article

作者: Valenzuela-Muñoz, Valentina ; Novoa, Beatriz ; Pereiro, Patricia ; Álvarez-Rodríguez, Margarita ; Gallardo-Escárate, Cristian ; Figueras, Antonio

PIM kinases are a family of serine/threonine protein kinases that potentiate the progression of the cell cycle and inhibit apoptosis. Because of this, they are considered to be proto-oncogenes, and they represent an interesting target for the development of anticancer drugs. In mammals, three PIM kinases exist (PIM-1, PIM-2 and PIM-3), and different inhibitors have been developed to block their activity. In addition to their involvement in cancer, some publications have reported that the PIM kinases have pro-viral activity, and different mechanisms where PIM kinases favour viral infections have been proposed. Zebrafish possess more than 300 Pim kinase members in their genome, and by using RNA-Seq analysis, we found a high number of Pim kinase genes that were significantly induced after infection with spring viraemia of carp virus (SVCV). Moreover, analysis of the miRNAs modulated by this infection revealed that some of them could be involved in the post-transcriptional regulation of Pim kinase abundance. To elucidate the potential role of the 16 overexpressed Pim kinases in the infectivity of SVCV, we used three different pan-PIM kinase inhibitors (SGI-1776, INCB053914 and AZD1208), and different experiments were conducted both in vitro and in vivo. We observed that the PIM kinase inhibitors had a protective effect against SVCV, indicating that, similar to what is observed in mammals, PIM kinases are beneficial for the virus in zebrafish. Moreover, zebrafish Pim kinases seem to facilitate viral entry into the host cells because when ZF4 cells were pre-incubated with the virus and then were treated with the inhibitors, the protective effect of the inhibitors was abrogated. Although more investigation is necessary, these results show that pan-PIM kinase inhibitors could serve as a useful treatment for preventing the spread of viral diseases.

2019-11-26·Blood advances2区 · 医学

The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN

2区 · 医学

Article

作者: Collins, Robert J. ; Pandey, Garima ; Epling-Burnette, Pearlie K. ; Mazzacurati, Lucia ; Koblish, Holly K. ; Amin, Narmin E. ; Reuther, Gary W. ; Lambert-Showers, Que T. ; Stubbs, Matthew C. ; Zhang, Ling

Key Points:

INCB053914 and ruxolitinib synergize to induce apoptosis of JAK2V617F-driven cells and to inhibit neoplastic growth of primary MPN cells. INCB053914 antagonizes ruxolitinib persistence in an in vivo MPN model.

项与 Uzansertib 相关的新闻（医药）

2023-02-15

·生物谷

重磅综述！科学家最新总结了一种蛋白激酶在血液系统肿瘤中的分子和临床研究进展

PIM激酶(Moloney白血病病毒的前病毒整合位点)是一个丝氨酸/苏氨酸蛋白激酶家族，在细胞发育、免疫调节和肿瘤发生中发挥作用。对原始Pim-1的早期研究导致发现Pim-1家族在淋巴瘤中的致癌作用。 PIM激酶(Moloney白血病病毒的前病毒整合位点)是一个丝氨酸/苏氨酸蛋白激酶家族，在细胞发育、免疫调节和肿瘤发生中发挥作用。对原始Pim-1的早期研究导致发现Pim-1家族在淋巴瘤中的致癌作用。尽管Pim-2与Pim-1只有55%的氨基酸同源性，但它被认为是Pim-1的补偿蛋白，因为它有非常相似的激酶域。该家族的第三个成员，pim-3，被发现催化组蛋白磷酸化和自磷酸化。这三种Pim蛋白都可以磷酸化丝氨酸和苏氨酸氨基酸，并且可以激活相似的细胞通路。这使得研究人员相信，单个Pim激酶是代偿性的，因此一个Pim激酶的丢失可以通过表达另一个Pim激酶来缓解。原文链接: https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-023-01721-1 近日，来自堪萨斯大学医学中心的研究者们在Molecular Cancer杂志上发表了题为“Targeting Pim kinases in hematological cancers: molecular and clinical review”的综述性文章，该研究总结了靶向Pim激酶在血液系统肿瘤中的分子和临床研究进展几十年的研究已经认识到Pim激酶在淋巴增生性疾病中的坚实作用。在JAK/STAT和酪氨酸激酶受体信号转导之后，Pim激酶经常上调，调节细胞的增殖、存活、代谢、细胞转运和信号转导。靶向Pim激酶是一种有趣的方法，因为Pim激酶的敲除会导致体内的非致命性表型，这表明临床抑制Pim可能有较少的副作用。此外，ATP结合位点提供了独特的特性，可用于开发针对一种或所有Pim异构体的小分子抑制剂。这篇综述对Pim激酶的表达及其与血液癌的关系进行了进一步的研究。对目前和过去的临床试验和Pim激酶抑制剂的体外特性进行了综述，并讨论了未来的发展方向。目前的研究表明，当与多种药物靶向治疗相结合时，Pim激酶抑制可能是最有价值的。骨髓增殖性肿瘤中Pim激酶活性升高的细胞机制原文链接: https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-023-01721-1 使用第一代Pim抑制剂的临床试验未能显著减轻患者的疾病负担或减轻化疗耐药性。此外，较高剂量的Pim抑制剂可能会产生非靶点效应，并可能导致不良反应，包括心脏事件、胃肠道问题、发热性中性粒细胞减少症和皮疹等。较新的、高度特异的Pim激酶抑制剂，如PIM447、UZANSERTIB和TP-3654可以克服这些问题，允许PIM在较低浓度下靶向。另一种选择是通过单抗Pim抗体治疗或间接靶向Pim激酶调节因子来直接靶向Pim激酶。在一些白血病细胞的细胞表面发现了Pim-1，这种细胞可以被单抗Pim-1(mPim-1)靶向治疗而失去增殖。未来的研究仍然需要委派单独的Pim亚型的特定作用，它们的下游靶点，以及如何调节Pim以更精确地改进治疗方案。然而，大量使用Pim抑制剂进行的临床前和临床试验表明，在淋巴增生性疾病和实体瘤中靶向Pim途径具有临床意义。（生物谷 Bioon.com）参考文献 Marcia Bellon et. Targeting Pim kinases in hematological cancers: molecular and clinical review. Mol Cancer. 2023 Jan 25;22(1):18. doi: 10.1186/s12943-023-01721-1.

临床研究

100 项与 Uzansertib 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床2期	美国	Incyte Corp.	2015-12-29
复发性弥漫性大B细胞淋巴瘤	临床1期	美国	Incyte Corp.	2018-12-03
难治性弥漫性大 B 细胞淋巴瘤	临床1期	美国	Incyte Corp.	2018-12-03

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02587598 (Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914, Pubmed \| Clin Lymphoma Myeloma Leuk)	临床1/2期	血液肿瘤	-	INCB053914 alone	鬱窪淵遞獵製窪壓製鬱(艱獵願淵願鹽壓廠衊壓) = most commonly ALT/AST-elevated 艱夢窪襯醖鬱獵鏇糧網 (鏇壓願廠糧遞構願鹽築 ) 更多	不佳	2023-09-01
				INCB053914 + cytarabine
NCT02587598 (ASH2017) 人工标引	临床1/2期	血液肿瘤	39	INCB053914 (TGA)	遞構衊鹹製鏇餘鏇蓋構(網顧繭壓範鏇築網襯糧) = 繭積壓築齋顧糧築鏇遞齋襯鏇鹹觸鏇鏇遞憲淵 (憲簾鏇觸廠構築鏇繭選 )	积极	2017-12-07
				INCB053914 (TGB)	遞構衊鹹製鏇餘鏇蓋構(網顧繭壓範鏇築網襯糧) = 構壓鏇齋遞艱構憲蓋簾齋襯鏇鹹觸鏇鏇遞憲淵 (憲簾鏇觸廠構築鏇繭選 )