GSK-2636771(GSK-2636771) - 药物靶点：GPR39 x PI3Kβ_在研适应症：肿瘤，转移性黑色素瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

GPR39 x PI3Kβ

作用方式

激动剂、抑制剂

作用机制

GPR39 激动剂(G protein-coupled receptor 39 agonists)、PI3Kβ抑制剂(磷脂酰肌醇-3激酶β抑制剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病

在研适应症

肿瘤转移性黑色素瘤

非在研适应症

晚期恶性实体瘤转移性去势抵抗性前列腺癌前列腺癌+ [1]

原研机构

GSK Plc

在研机构

GSK Plc

Merck Sharp & Dohme Corp.

非在研机构

Yonsei University Health System

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C22H22F3N3O3

InChIKeyXTKLTGBKIDQGQL-UHFFFAOYSA-N

CAS号1372540-25-4

关联

8

项与 GSK-2636771 相关的临床试验

NCT03131908

/ Active, not recruiting临床1/2期IIT

Phase I/II Study of the Selective PI3K-Beta Inhibitor GSK2636771 in Combination With Pembrolizumab in Patients With Metastatic Melanoma and PTEN Loss

The goal of this clinical research study is to learn if GSK2636771 given in combination with pembrolizumab can help to control the disease in patients with refractory (has not responded to treatment) metastatic melanoma. The safety of this drug combination will also be studied.
This is an investigational study. Pembrolizumab is FDA approved and commercially available and FDA approved for the treatment of several types of cancer, including melanoma. GSK2636771 is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work.
Up to 41 participants will be enrolled in this study. All will take part at MD Anderson.

开始日期2017-07-17

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+4]

NCT04439149

/ Active, not recruiting临床2期IIT

MATCH Treatment Subprotocol N: Phase II Study of PI3K Beta Specific Inhibitor, GSK2636771, in Patients With Tumors With PTEN Mutation or Deletion, With PTEN Expression on IHC

This phase II MATCH treatment trial identifies the effects of GSK2636771 in patients whose cancer has a genetic change called PTEN mutation or deletion. GSK2636771 may block a protein called PI3K-beta, which may be needed for growth of cancer cells that express PTEN mutations. Researchers hope to learn if GSK2636771 will shrink this type of cancer or stop its growth.

开始日期2016-02-25

申办/合作机构

National Cancer Institute

NCT04439188

/ Active, not recruiting临床2期IIT

MATCH Treatment Subprotocol P: Phase II Study of PI3K Beta Specific Inhibitor, GSK2636771, in Patients With Tumors With PTEN Loss by IHC

This phase II MATCH treatment trial identifies the effects of GSK2636771 in patients whose cancer has a complete loss of PTEN expression. GSK2636771 may block a protein called PI3K-beta, which may be needed for growth of cancer cells with complete loss of PTEN expression. Researchers hope to learn if GSK2636771 will shrink this type of cancer or stop its growth.

开始日期2016-02-25

申办/合作机构

National Cancer Institute

100 项与 GSK-2636771 相关的临床结果

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100 项与 GSK-2636771 相关的转化医学

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100 项与 GSK-2636771 相关的专利（医药）

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18

项与 GSK-2636771 相关的文献（医药）

2024-01-20·Journal of Clinical Oncology

Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study

Article

作者: Lee, Choong-Kun ; Park, Sook Ryun ; Zang, Dae Young ; Nam, Chung Mo ; Rha, Sun Young ; Hwang, In Gyu ; Chung, Hyun Cheol ; Jung, Minkyu ; Kim, Hyo Song ; Kim, Hyunki ; Koo, Dong-Hoe ; Bae, Woo Kyun ; Jeung, Hei Cheul ; Lee, Hyun Woo ; Park, Sejung

PURPOSE This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC). PATIENTS AND METHODS Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cβ inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti–PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus–related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety. RESULTS A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08). CONCLUSION Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

2022-05-01·Advanced Healthcare Materials2区 · 材料科学

Arming Immune Cell Therapeutics with Polymeric Prodrugs

2区 · 材料科学

Article

作者: Srinivasan, Selvi ; Blumenthal, Ian ; Crane, Courtney A. ; Chiefari, John ; Stayton, Patrick S. ; Huang, Fei ; Roy, Debashish ; Montgomery, Kate S. ; Gardell, Jennifer L. ; Kreuser, Shannon A. ; Brempelis, Katherine J. ; Matthaei, James F. ; López, Ciana L. ; Jensen, Michael C.

AbstractEngineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune‐suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering is developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand‐tagged polymeric prodrugs, termed “drugamers.” The fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate prodrug monomers of the phosphoinositide‐3‐kinase inhibitor, PI‐103. The extended release of PI‐103 from the drugamer sustains antiproliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second fluorescein‐drugamer. This drugamer incorporates a small molecule estrogen analog, CMP8, which stabilizes a degron‐tagged transgene to provide temporal regulation of protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene‐activating small molecule prodrugs.

2021-10-01·Clinical Cancer Research1区 · 医学

A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

1区 · 医学

Article

作者: Gorczyca, Michele ; Vaishampayan, Ulka N. ; Henson, Lynn ; Dorff, Tanya B. ; Tolson, Jerry ; Roy-Ghanta, Sumita ; Pantuck, Allan J. ; de Bono, Johann S. ; York, Whitney ; Sarker, Debashis ; Ganji, Gopinath ; Aparicio, Ana M. ; Vasist, Lakshmi ; Dawson, Nancy A.

AbstractPurpose:In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance.Patients and Methods:In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate.Results:Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug–drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2–71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%.Conclusions:Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

100 项与 GSK-2636771 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11795

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
转移性黑色素瘤	临床2期	美国	Merck Sharp & Dohme Corp.	2017-07-17
转移性黑色素瘤	临床2期	美国	GSK Plc	2017-07-17
肿瘤	临床2期	-	GSK Plc	-
前列腺癌	临床前	英国	GSK Plc	-
前列腺癌	临床前	美国	GSK Plc	-
胃癌	药物发现	韩国	Yonsei University Health System	2016-01-10
转移性去势抵抗性前列腺癌	药物发现	英国	GSK Plc	2014-11-13
晚期恶性实体瘤	药物发现	美国	GSK Plc	2011-11-10
晚期恶性实体瘤	药物发现	韩国	GSK Plc	2011-11-10
晚期恶性实体瘤	药物发现	英国	GSK Plc	2011-11-10

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临床结果

适应症

分期

评价

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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


NCT02951091 (ASCO2022) 人工标引	临床2期	进展期胃腺癌二线	329	biomarker group	(醖衊網選構簾廠壓夢齋) = 築積襯淵築獵醖築顧簾獵蓋獵鬱夢觸繭鬱繭積 (蓋獵齋構膚壓艱廠積觸, 3.2 ~ 4.3) 更多	不佳	2022-06-02
				paclitaxel+afatinib (EGFR 2+/3+ patients)	(醖衊網選構簾廠壓夢齋) = 鏇艱窪選廠蓋獵衊鑰觸獵蓋獵鬱夢觸繭鬱繭積 (蓋獵齋構膚壓艱廠積觸, 3.3 ~ 4.6) 更多
NCT01458067 (ASCO2022) 人工标引	临床1/2期	转移性去势抵抗性前列腺癌	12	GSK2636771+pembrolizumab	(築蓋網網鬱齋積範糧積) = The RP2D was identified at 200mg PO QD of GSK2636771 + pembrolizumab 200mg IV Q3W. 築顧願構選餘鏇憲蓋範 (窪範鹹憲淵鑰築繭餘淵 ) 更多	积极	2022-06-02
NCT02951091 \| NCT02615730 (ASCO_GI2022)	临床2期	进展期胃腺癌二线 PI3K/Akt pathway alterations \| EBV-related \| dMMR/MSI-H ... 更多	54	GSK2636771	(選網簾襯獵繭膚鹽壓淵) = 齋襯範鑰鏇積鹽憲憲鹽壓窪選壓積壓積鹽糧繭 (築觸糧衊選醖壓築糧醖 ) 更多	-	2022-01-19
				Paclitaxel	(選網簾襯獵繭膚鹽壓淵) = 淵遞鬱鹹製網鑰鑰糧淵壓窪選壓積壓積鹽糧繭 (築觸糧衊選醖壓築糧醖 ) 更多
NCT01458067 (ESMO 12021 \| ESMO 22021) 人工标引	临床1/2期	HR阳性/HER2低表达实体瘤 \| 黑色素瘤	27	GSK2636771+pembrolizumab	(願願艱築顧艱鏇衊艱衊) = G771 (200 mg PO QD) 鑰衊膚膚鑰遞蓋鏇糧廠 (淵繭網衊餘壓膚餘衊蓋 ) 更多	积极	2021-09-16
NCT02215096 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	转移性去势抵抗性前列腺癌	37	enzalutamide+GSK2636771	製鏇網壓顧憲齋廠蓋淵(齋廠獵憲廠醖夢蓋鏇觸) = 鹽選廠繭觸襯淵遞鏇淵醖衊鬱憲憲齋鏇衊餘鏇 (夢遞鬱齋糧淵範範鏇淵, 28.2 ~ 71.8) 更多	不佳	2021-07-19
NCT02615730 (SO-10, ESMO_GI2021)	临床1/2期	晚期胃癌 PTEN expression	42	GSK2636771 300mg once daily + paclitaxel 80mg/m2	(繭襯艱窪網願築艱繭簾) = 衊積餘餘製淵願窪觸襯選憲築築膚襯壓範衊壓 (製積夢積鹽鑰餘顧壓窪, 11.1 ~ 13.2) 更多	-	2021-07-03
				GSK2636771 200mg once daily + paclitaxel 80mg/m2	(繭襯艱窪網願築艱繭簾) = 淵範鏇顧夢膚鬱鹹衊淵選憲築築膚襯壓範衊壓 (製積夢積鹽鑰餘顧壓窪, 26.2 ~ 40.7) 更多
NCT02215096 (CTgov)	临床1期	转移性去势抵抗性前列腺癌	37	Enzalutamide (Enzalutamide Only (run-in Period))	衊夢願獵襯廠製獵選選(衊衊衊夢憲觸窪窪製簾) = 淵壓淵艱構鹽遞築繭遞製範鬱鹹餘窪艱齋醖繭 (繭願遞鹹糧齋遞夢築觸, 遞窪觸築鏇鏇襯積醖願 ~ 鹹膚廠鹽簾襯夢艱鏇範) 更多	-	2020-10-22
				Enzalutamide+GSK2636771 (GSK2636771 200mg/Enzalutamide 160mg Escalation)	衊鹽築積鬱蓋鹹鬱構膚(築鏇獵齋壓淵觸鹽淵築) = 齋夢鹽構獵築積餘鏇齋壓獵顧顧觸顧獵醖簾鹹 (觸願壓選顧憲糧憲製齋, 鹽衊鬱積鑰衊醖遞衊鑰 ~ 壓膚襯衊觸選鬱蓋齋憲) 更多
NCT03131908 (ASCO 12020 \| ASCO 22020) 人工标引	临床1/2期	转移性黑色素瘤 PTEN Loss	13	GSK-2636771 200 mg+pembrolizumab 200mg (DL-1)	(繭構網鑰鏇廠築遞顧範) = DL-1 was declared RP2D at 200mg 鏇窪醖艱齋築艱積糧夢 (獵壓鏇醖簾簾範顧鹹繭 )	积极	2020-05-29
				GSK-2636771 300 mg+pembrolizumab 200mg (DL1)
NCT02465060 (NCI-MATCH, ESMO2018) 人工标引	临床2期	肿瘤 PTEN Deletion \| PTEN Mutation \| PTEN Loss	56	GSK-2636771 (PTEN mutation/deletion (mut/del))	(蓋顧憲網鑰鹹餘獵齋範) = 簾範醖餘夢願艱獵糧顧築衊淵範簾鬱構鏇積觸 (膚鏇鬱鏇簾膚鹹夢襯鏇 ) 更多	积极	2018-10-20
				GSK-2636771 (PTEN protein loss)	(蓋顧憲網鑰鹹餘獵齋範) = 衊淵獵鹽顧範簾糧淵廠築衊淵範簾鬱構鏇積觸 (膚鏇鬱鏇簾膚鹹夢襯鏇 ) 更多
AACR2015	临床1期	晚期癌症	62	GSK2636771 400 mg QD	(衊網遞廠襯鹹憲鑰願築) = 鑰築鏇獵獵鬱廠憲衊顧顧襯網鹽選醖醖齋簾鏇 (淵遞構鹹淵鑰憲膚範製 )	-	2015-08-01