PF-4878691(PF-4878691) - 药物靶点：TLR7_专利_临床

概要

基本信息

药物类型

小分子化药

别名

IMDZQ、3M-852A、852A

+ [2]

靶点

TLR7

作用方式

激动剂

作用机制

TLR7激动剂(Toll样受体7激动剂)

治疗领域

肿瘤免疫系统疾病感染+ [6]

在研适应症-

非在研适应症

急性淋巴细胞白血病急性髓性白血病巴雷特食管+ [15]

原研机构

3M Health Care, Inc.

在研机构-

非在研机构

Pfizer Inc.

Kindeva Drug Delivery LP

3M Health Care, Inc.

权益机构-

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

结构/序列

分子式C17H23N5O2S

InChIKeyYZOQZEXYFLXNKA-UHFFFAOYSA-N

CAS号532959-63-0

关联

7

项与 PF-4878691 相关的临床试验

NCT00810758

/ Completed临床1期

A Phase 1, Randomized, Placebo Controlled, Blinded (3rd Party Open), Sequential, Multiple-Dose Escalation Study To Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-04878691 In Healthy Volunteers

To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple oral doses of PF-04878691.

开始日期2009-01-01

申办/合作机构

Pfizer Inc.

NCT00386594

/ TerminatedN/AIIT

Pilot Study of Oral 852A for Elimination of High-Grade Dysplasia in Barrett's Esophagus

Barrett's esophagus with high-grade dysplasia is a premalignant condition caused by chronic reflux of gastric contents into the esophagus. High-grade dysplasia is the same as carcinoma-in-situ. If untreated, patients with this condition are at high risk for developing cancer of the esophagus. Cancer of the esophagus is a miserable disease that is difficult to treat and about 95% fatal after 5 years. To prevent progession to cancer of the esophagus several interventions are available and they include surgery, Photofrin photodynamic therapy, endoscopic mucosal resection and endoscopic thermal therapy. All of these modalities are uncomfortable, expensive and have associated risks. The oral agent, 852A stimulates the innate immune system in such a way as to eliminate early cancer. A similar dermatologic drug(imiquimod) is approved for treating the premalignant condition, actinic keratosis. If local therapy with imiquimod can eliminate a premalignant lesion in the skin, a similar acting drug should be able to do the same for a premalignant lesion in the lining of the esophagus. This study is designed to test that hypothesis.

开始日期2006-10-01

申办/合作机构-

NCT00319748

/ Completed临床2期IIT

Phase II Study of 852A Administered Subcutaneously in Patients With Metastatic Refractory Breast, Ovarian, Endometrial and Cervical Cancers

The purpose of this study is to evaluate the anti-tumor activity of 852A when used to treat metastatic breast, ovarian, endometrial or cervical cancer not responding to standard treatment.

开始日期2006-04-01

申办/合作机构

University of Minnesota Masonic Cancer Center

[+1]

100 项与 PF-4878691 相关的临床结果

登录后查看更多信息

100 项与 PF-4878691 相关的转化医学

登录后查看更多信息

100 项与 PF-4878691 相关的专利（医药）

登录后查看更多信息

18

项与 PF-4878691 相关的文献（医药）

2011-06-01·Clinical pharmacology and therapeutics2区 · 医学

The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691)

2区 · 医学

Article

作者: R Webster ; TP Corey ; E van der Ryst ; V Kumar ; M Perros ; BE Souberbielle ; J Rawal ; Fidock ; K Rana ; M Westby ; JB Cheng ; O Delpuech‐Adams ; C Craig ; P Colman ; C Laxton ; S Srinivasan ; N Horscroft ; K Wright

Hepatitis C virus (HCV) infection is an issue of global concern, and studies are ongoing to identify new therapies that are both effective and safe. PF-4878691 is a Toll-like receptor 7 (TLR7) agonist modeled so as to dissociate its antiviral activities from its inflammatory activities. In a proof-of-mechanism study in healthy volunteers who received doses of 3, 6, and 9 mg of PF-4878691 twice a week for 2 weeks, PF-4878691 induced biomarkers of the immune and interferon (IFN) responses in a dose-dependent and dose-frequency-related manner. A novel finding was induction of TLR7 expression in vivo in response to PF-4878691, leading to an amplified biomarker response. A nonresponder at the 9-mg dose had a polymorphism in the IFN-α receptor 1 subunit (Val168Leu). Two subjects who had received 9-mg doses experienced serious adverse events (SAEs), characterized by flu-like symptoms, hypotension, and lymphopenia, leading to early termination of the study. TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection.

2010-12-01·Cancer immunology, immunotherapy : CII2区 · 医学

Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers

2区 · 医学

Article

作者: Miller, Jeffrey S ; Carson, Linda F ; Judson, Patricia L ; Cooley, Sarah ; Weigel, Brenda ; Curtsinger, Julie ; Ghebre, Rahel ; Downs, Levi S ; Geller, Melissa A ; Panoskaltsis-Mortari, Angela ; Argenta, Peter A

BACKGROUND:

The primary objective was to study the antitumor activity of prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer. Secondary objectives included assessment of safety and immune system activation.

METHODS:

Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m(2) of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m(2)/week to a maximum of 1.2 mg/m(2). Serum was collected to assess immune activation.

RESULTS:

Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (2 asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One who had stable disease (SD) following 24 doses received 17 additional doses. A cervix patient with SD following 24 doses received chemotherapy after progressing 3 months later, and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed.

CONCLUSIONS:

In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule, 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest, but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; 852A should be used cautiously in heavily pretreated patients.

2010-07-15·Cancer biology & therapy3区 · 医学

Potentiation of the antitumor effects of imidazoquinoline immune response modifiers by cyclophosphamide

3区 · 医学

Article

作者: Tomai, Mark A. ; Dumitru, Calin D. ; Lipson, Kenneth E. ; Antonysamy, Mary A.

The aim of the current study was to evaluate the influence of chemotherapeutic drugs on immunotherapy with Imidazoquinoline Toll-like Receptor (TLR) agonists in cancer. First, the previously described antitumor efficacy of TLR agonists [i.e. a TLR7 agonist (852A) and a dual TLR7/8 agonist (3M-011)] was confirmed in additional cancer models, and second the therapeutic potential of TLR agonists in combination with cyclophosphamide was investigated. The antitumor potential was evaluated against a panel of syngeneic tumor models; namely B16-F10 melanoma, M3 melanoma and MC-26 colon carcinoma. Systemic administration of either 3M-011 or 852A in these various syngeneic models induced significant antitumor activity as evidenced by delays in tumor growth curves. Combination of cyclophosphamide with either 3M-011 or 852A demonstrated that cyclophosphamide does not negatively interfere with the TLR agonist's antitumor effects, but may, depending on the dosing schedule, to actually potentiate the effect. These findings suggest that the immunomodulatory TLR agonists may be used in combination with cytotoxic agents in the treatment of cancer.

100 项与 PF-4878691 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12476

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
转移性乳腺癌	临床2期	美国	Pfizer Inc.	2006-04-01
子宫颈转移癌	临床2期	美国	Pfizer Inc.	2006-04-01
转移性子宫内膜恶性肿瘤	临床2期	美国	Pfizer Inc.	2006-04-01
卵巢上皮癌	临床2期	美国	Pfizer Inc.	2006-04-01
复发性子宫内膜癌	临床2期	美国	Pfizer Inc.	2006-04-01
子宫颈腺癌	临床2期	美国	Pfizer Inc.	2006-04-01
急性淋巴细胞白血病	临床2期	美国	Pfizer Inc.	2006-01-01
急性髓性白血病	临床2期	美国	Pfizer Inc.	2006-01-01
慢性淋巴细胞白血病	临床2期	美国	Pfizer Inc.	2006-01-01
霍奇金淋巴瘤	临床2期	美国	Pfizer Inc.	2006-01-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00276159 (CTgov)	临床2期	霍奇金淋巴瘤 \| 急性髓性白血病 \| 慢性淋巴细胞白血病 ... 更多	6	852A	觸鬱遞顧衊憲願鏇繭糧 = 積網遞鹹鑰鹹鑰願齋壓鹽築醖鑰衊鹹鹽願顧齋 (鹹餘鏇廠觸鬱願構廠積, 築構獵艱獵廠範襯獵廠 ~ 製觸鹽構淵艱蓋範築醖) 更多	-	2010-05-05
NCT00319748 (CTgov)	临床2期	卵巢癌 \| 子宫内膜癌 \| 子宫颈转移癌 ... 更多	15	852A (Patients With Ovarian Cancer)	壓築鬱醖鹹憲願鹽糧衊 = 壓窪鹹鬱遞簾製鹽糧鏇糧簾網積顧糧糧鹹鏇繭 (繭餘鬱夢觸範觸鑰齋艱, 壓艱壓製襯積鏇襯夢衊 ~ 簾夢廠醖鬱鏇艱衊襯窪) 更多	-	2009-09-25
NCT00319748 (CTgov)	临床2期	卵巢癌 \| 子宫内膜癌 \| 子宫颈转移癌 ... 更多	15	852A (Patients Treated With 852A)	鏇繭構鹽製網鹹膚構繭(窪築願壓廠憲衊遞獵糧) = 糧鑰範選鏇鏇鹹窪膚鏇獵獵選獵積範願艱鏇蓋 (壓夢衊鹽餘襯壓壓壓鏇, 窪獵積觸廠艱醖觸鹽繭 ~ 蓋淵艱淵顧壓範鏇願襯) 更多	-	2009-09-25