更新于：2024-08-04
PF-4136309
更新于：2024-08-04
概要
基本信息
在研机构- |
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- |
结构
分子式C29H31F3N6O3 |
InChIKeyZNSVOHSYDRPBGI-LXWOLXCRSA-N |
CAS号1341224-83-6 |
关联
5
项与 PF-4136309 相关的临床试验PHASE 1B/2 STUDY OF PF-04136309 IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA
A Phase 1, Randomized, Open Label, Single Dose, 2-period Crossover Study To Evaluate Food Effect On The Pharmacokinetics Of Pf-04136309 In Healthy Subjects
Phase IB Study of FOLFIRINOX Plus PF-04136309 in Patients With Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma
100 项与 PF-4136309 相关的临床结果
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100 项与 PF-4136309 相关的转化医学
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100 项与 PF-4136309 相关的专利（医药）
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4
项与 PF-4136309 相关的文献（医药）2021-01-01Journal of Cancer3区 · 医学
GOLM1 Drives Colorectal Cancer Metastasis by Regulating Myeloid-derived Suppressor Cells
3区 · 医学
ArticleOA
作者: Yu, Jiao ; Cao, Ximing ; Jin, Long ; Zhao, Shuhong ; Dang, Yunzhi ; Wang, Qing
Colorectal cancer (CRC) is the most common digestive neoplasms worldwide, metastasis and recurrence still account for the leading cause for the high mortality rate, but the exact mechanisms remain unclear. More and more evidence has indicated that the deregulation of GOLM1 plays a crucial role in cancer progression. Here, we reported a novel role of GOLM1 in promoting CRC metastasis. In this study, the expression of GOLM1 was detected in human CRC cohort. The function of GOLM1 in CRC metastasis was analyzed by in vivo cecum orthotopic model. We found that the expression of GOLM1 was significantly increased in CRC tissues than adjacent nontumor. Overexpression GOLM1 can promote CRC immune escape and metastasis by recruiting of myeloid-derived suppressor cells (MDSCs) at the same time. PF-04136309, a small molecule and specific inhibitor of CCR2 can largely suppressed GOLM1-mediated CRC metastasis. These results suggest that GOLM1 can promote CRC metastasis and is a prognostic biomarker in human CRC.
2020-06-01Investigational new drugs
Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma
Article
作者: Ryan, David P ; Ganguly, Bishu ; Jacobs, Ira A ; Yin, Donghua ; Gamelin, Eric C ; Wolpin, Brian M ; O'Reilly, Eileen M ; Lowery, Maeve A ; Britten, Carolyn D ; Linehan, David C ; Taylor, Carrie T ; Joh, Tenshang ; Belt, Brian A ; Bullock, Andrea J ; Noel, Marcus
Summary:
Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC. Methods Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) administered on days 1, 8, and 15 of each 28-day cycle. The primary objectives were to evaluate safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the recommended phase II dose (RP2D) of PF-04136309. Results In all, 21 patients received PF-04136309 at a starting dose of 500 mg or 750 mg BID. The RP2D was identified to be 500 mg BID. Of 17 patients treated at the 500 mg BID starting dose, three (17.6%) experienced a total of four DLTs, including grade 3 dysesthesia, diarrhea, and hypokalemia and one event of grade 4 hypoxia. Relative to the small number of patients (n = 21), a high incidence (24%) of pulmonary toxicity was observed in this study. The objective response rate for 21 patients was 23.8% (95% confidence interval: 8.2–47.2%). Levels of CD14 + CCR2+ inflammatory monocytes (IM) decreased in the peripheral blood, but did not accumulate in the bone marrow. Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine. ClinicalTrials.gov identifier: NCT02732938.
2016-05-01The Lancet. Oncology1区 · 医学
Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial
1区 · 医学
Article
作者: Tan, Benjamin R ; Fields, Ryan C ; Belt, Brian A ; Linehan, David C ; Sanford, Dominic E ; Panni, Roheena Z ; Goedegebuure, S Peter ; Hawkins, William G ; Nywening, Timothy M ; Nieman, Rebecca K ; DeNardo, David G ; Yano, Motoyo ; Lockhart, A Craig ; Wang-Gillam, Andrea ; Lim, Kian-Huat ; Cusworth, Brian M ; Toriola, Adetunji T ; Fowler, Kathryn J ; Suresh, Rama ; Worley, Lori A ; Strasberg, Steven M
BACKGROUND:
In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil).
METHODS:
We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022.
RESULTS:
Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease.
INTERPRETATION:
CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable.
FUNDING:
Washington University-Pfizer Biomedical Collaborative.
1
项与 PF-4136309 相关的新闻（医药）2022-07-18
抗体小分子药物免疫疗法
100 项与 PF-4136309 相关的药物交易
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研发状态
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 转移性胰腺导管腺癌 | 临床2期 | 美国 | 2016-05-04 | |
| 慢性丙型肝炎 | 临床2期 | 中国香港 | 2011-01-17 | |
| 慢性丙型肝炎 | 临床2期 | 印度 | 2011-01-17 | |
| 慢性丙型肝炎 | 临床2期 | 新加坡 | 2011-01-17 | |
| 慢性丙型肝炎 | 临床2期 | 韩国 | 2011-01-17 | |
| 慢性丙型肝炎 | 临床2期 | 中国台湾 | 2011-01-17 | |
| 膝关节炎 | 临床2期 | 美国 | 2008-08-05 | |
| 膝关节炎 | 临床2期 | 韩国 | 2008-08-05 | |
| 局部晚期胰腺腺癌 | 临床1期 | 美国 | 2012-04-01 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
临床2期 | 24 | (PF-04136309) | 齋鬱齋壓廠範觸襯範餘(廠鬱觸夢製艱築簾廠構) = 蓋齋廠淵糧廠膚簾範壓 觸願願齋鑰製構構獵蓋 (淵選觸夢簾鏇齋獵獵壓, 醖築繭範憲齋憲網積糧 ~ 淵鬱網觸網蓋構簾製遞) 更多 | - | 2023-07-27 | ||
Placebo (Placebo) | 齋鬱齋壓廠範觸襯範餘(廠鬱觸夢製艱築簾廠構) = 襯廠遞觸壓廠顧餘簾簾 觸願願齋鑰製構構獵蓋 (淵選觸夢簾鏇齋獵獵壓, 衊遞鏇築鏇襯壓顧膚廠 ~ 遞蓋膚顧鏇遞積餘鏇壓) 更多 | ||||||
临床2期 | 159 | (PF-04136309) | 觸淵範繭鏇襯夢艱壓鑰(衊襯遞簾選夢壓糧鏇壓) = 餘鏇簾積窪鑰醖網築糧 範鬱網夢網壓壓願築餘 (積憲憲獵夢憲製襯鬱簾, 齋憲鹹願範餘積鬱淵鑰 ~ 襯積窪製衊鑰遞夢鹹觸) 更多 | - | 2021-07-13 | ||
Placebo (Placebo) | 觸淵範繭鏇襯夢艱壓鑰(衊襯遞簾選夢壓糧鏇壓) = 築顧襯選範築鏇選範遞 範鬱網夢網壓壓願築餘 (積憲憲獵夢憲製襯鬱簾, 鹽廠築鹽鏇襯願獵網膚 ~ 艱醖網遞壓鬱簾廠鑰糧) 更多 | ||||||
临床1期 | 21 | 壓獵齋艱鏇夢選餘衊構(網鏇鬱願夢餘餘餘簾鹹) = PF-04136309 500 mg BID 繭膚艱鑰齋蓋鏇鏇網廠 (獵廠觸蓋衊選餘網獵襯 ) 更多 | 不佳 | 2020-06-01 | |||
临床1期 | 转移性胰腺腺癌 一线 | 21 | (all pts) | 顧膚艱餘顧襯夢糧築廠(糧願築襯積築蓋築糧積) = Cohort 1, starting dose level: 1 grade 3 drug-related DLT (cognitive disorder), 1 grade 2 and 2 grade 1 rashes. Cohort 2 (1 dose level reduction): 4 (23.5%) grade 3 drug-related DLT (1 scalp dysesthesia, 1 ALT-AST, 1 pneumonia, 1 pneumonitis) 壓網願鹹蓋積廠範壓獵 (夢遞壓淵淵衊遞廠鹹餘 ) 更多 | 积极 | 2017-09-09 |
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