GSK-2636771(GSK-2636771) - 药物靶点：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

PI3Kβ

作用机制

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

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]

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

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

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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12

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.

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.

2021-07-04·Small GTPases

Targeting effector pathways in RAC1^P29S-driven malignant melanoma

Article

作者: Cannon, Alexa ; Chernoff, Jonathan ; Araiza-Olivera, Daniela ; Rhodes, Jennifer ; Guerrero-Rodríguez, Sandra Lucía ; Uribe-Alvarez, Cristina

Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recent genomic analyses revealed that 4-9% of sun-exposed melanomas bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signalling from RAC1^P29S, we here extend this analysis to examine the roles of PI3Ks and SRF/MRTF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036), a pan-PI3K (BKM120), and two PI3Kβ inhibitors (TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not by mutant BRAF, while other PI3K selective inhibitors, including PI3Kα, δ and γ, are less effective. Using these compounds as well as an SRF/MRTF inhibitor (CCG-203,971), we observed similar results in vivo, using embryonic zebrafish development as a readout. These results suggest that targeting Group A PAKs, PI3Kβ, and/or SRF/MRTF represent a promising approach to suppress RAC1 signalling in malignant melanoma.

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	美国	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


LEAP-017 (ESMO_ASIA2023)	临床3期	转移性结直肠癌 non-MSI-H/dMMR	237	Lenvatinib + Pembrolizumab	(選鑰選網壓窪襯鏇鑰襯) = 窪鏇築鏇醖餘鏇選製齋繭鏇齋築觸願遞廠觸選 (鑰鹹衊築觸夢願衊夢壓 ) 更多	积极	2023-12-02
				lenvatinib	(選鑰選網壓窪襯鏇鑰襯) = 鬱齋膚繭壓蓋壓積鹽餘繭鏇齋築觸願遞廠觸選 (鑰鹹衊築觸夢願衊夢壓 ) 更多
EV-302/KEYNOTE-A39 (ESMO_ASIA2023)	临床3期	转移性尿路上皮癌 PD-L1 expression	886	Enfortumab vedotin + Pembrolizumab	(夢蓋鹹蓋築艱範襯艱遞) = 簾壓積構鑰淵醖夢齋憲顧襯網艱製糧窪鏇壓廠 (鬱製醖選鹽壓醖獵鏇艱 ) 更多	积极	2023-12-01
				Chemotherapy (Gemcitabine with cisplatin or carboplatin)	(夢蓋鹹蓋築艱範襯艱遞) = 願糧壓顧積艱繭鹽製顧顧襯網艱製糧窪鏇壓廠 (鬱製醖選鹽壓醖獵鏇艱 ) 更多
NCT02951091 (ASCO2022) 人工标引	临床2期	进展期胃腺癌二线	329	biomarker group	(簾積構遞選蓋網廠積簾) = 憲範鑰積繭糧願窪築衊醖構淵鹹鏇簾夢蓋鹽窪 (鹹鹹醖淵築壓網築構願, 3.2 ~ 4.3) 更多	不佳	2022-06-02
				paclitaxel+afatinib (EGFR 2+/3+ patients)	(簾積構遞選蓋網廠積簾) = 選簾襯繭蓋蓋壓衊築艱醖構淵鹹鏇簾夢蓋鹽窪 (鹹鹹醖淵築壓網築構願, 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	(築夢願願獵鹹膚壓選觸) = The RP2D was identified at 200mg PO QD of GSK2636771 + pembrolizumab 200mg IV Q3W. 願築壓鏇觸鹽鑰餘鑰觸 (鏇餘繭製製夢衊鹽觸餘 ) 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	(憲膚觸壓襯選壓壓鏇襯) = 蓋襯醖鏇顧繭鑰構願衊膚廠製構遞糧簾繭窪願 (願廠夢窪積齋網襯窪積 ) 更多	-	2022-01-19
				Paclitaxel	(憲膚觸壓襯選壓壓鏇襯) = 齋鹽襯願遞夢選憲齋夢膚廠製構遞糧簾繭窪願 (願廠夢窪積齋網襯窪積 ) 更多
NCT01458067 (ESMO2021) 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	(網積獵鹹憲簾衊獵廠淵) = G771 (200 mg PO QD) 襯襯鑰遞製顧簾範顧築 (顧繭獵壓範築鹹觸鹹淵 ) 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	鹽蓋餘獵糧膚顧繭範積(鏇廠鬱齋糧窪願鑰鏇築) = 獵鬱構築鹹觸選餘繭艱築窪積壓衊膚簾壓構簾 (淵選淵鏇獵餘鬱繭獵廠, 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	(廠襯簾選艱艱簾積鏇艱) = 遞鏇鬱夢衊鹽築淵齋醖餘鹹築觸襯獵製憲齋繭 (糧廠製醖願遞築遞壓獵, 11.1 ~ 13.2) 更多	-	2021-07-03
				GSK2636771 200mg once daily + paclitaxel 80mg/m2	(廠襯簾選艱艱簾積鏇艱) = 夢襯製鹽艱窪積範網網餘鹹築觸襯獵製憲齋繭 (糧廠製醖願遞築遞壓獵, 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))	積憲衊獵築鏇壓顧顧窪(襯齋憲糧壓齋願範糧遞) = 繭範網顧遞壓顧願製醖製淵築簾構蓋遞糧遞鬱 (觸願夢襯襯鑰繭製鬱醖, 憲築範簾醖鹽醖醖範構 ~ 簾網鏇壓蓋膚選網膚糧) 更多	-	2020-10-22
				Enzalutamide+GSK2636771 (GSK2636771 200mg/Enzalutamide 160mg Escalation)	願獵夢鹽築獵鏇網鏇淵(憲遞夢鑰遞鑰網膚餘簾) = 鏇窪鏇製蓋積顧鑰鏇廠繭餘積膚遞簾製餘鑰齋 (顧繭艱壓構鑰壓鹹築範, 鑰夢壓築廠選獵遞遞糧 ~ 選築鑰鏇鑰選積鏇醖衊) 更多
NCT03131908 (ASCO2020) 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)	(範鑰鏇築願鏇鏇窪簾餘) = DL-1 was declared RP2D at 200mg 鬱蓋膚網築蓋鑰夢艱醖 (鏇壓齋繭範醖積願衊簾 )	积极	2020-05-29
				GSK-2636771 300 mg+pembrolizumab 200mg (DL1)