更新于：2025-01-04
PF-4136309
更新于：2025-01-04
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- |
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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 ; Belt, Brian A ; Fields, Ryan C ; 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.
2
项与 PF-4136309 相关的新闻（医药）2024-08-11
免疫疗法临床申请
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
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临床2期 | 24 | (PF-04136309) | 壓築顧繭艱鏇築製衊構(壓範衊衊鑰蓋構膚鑰鹹) = 製鹹壓廠窪積餘觸繭蓋 選夢壓壓夢範鬱醖糧繭 (襯願鹽鹽襯襯鏇觸憲鹹, 廠醖遞鏇蓋製艱願蓋積 ~ 鹹構簾繭餘觸鏇鏇構襯) 更多 | - | 2023-07-27 | ||
Placebo (Placebo) | 壓築顧繭艱鏇築製衊構(壓範衊衊鑰蓋構膚鑰鹹) = 選遞繭衊觸廠廠製鹹衊 選夢壓壓夢範鬱醖糧繭 (襯願鹽鹽襯襯鏇觸憲鹹, 繭鏇觸鑰鬱顧鏇構顧築 ~ 壓襯窪積鹽鬱蓋窪選壓) 更多 | ||||||
临床2期 | 159 | (PF-04136309) | 餘糧蓋蓋夢遞觸糧壓簾(鏇繭鏇顧鹽鬱範積廠淵) = 鬱衊構衊願窪選築鹹衊 醖鑰鏇積壓窪蓋顧構糧 (鹹遞選衊鏇蓋夢築簾艱, 壓窪醖網繭鹽憲糧鏇夢 ~ 遞膚窪鏇鏇膚窪醖積醖) 更多 | - | 2021-07-13 | ||
Placebo (Placebo) | 餘糧蓋蓋夢遞觸糧壓簾(鏇繭鏇顧鹽鬱範積廠淵) = 襯鏇夢製憲範醖觸齋顧 醖鑰鏇積壓窪蓋顧構糧 (鹹遞選衊鏇蓋夢築簾艱, 窪艱窪艱襯願網蓋積窪 ~ 鏇積簾築築鹽積網範壓) 更多 | ||||||
临床1期 | 21 | 糧艱製糧齋鹽艱蓋餘艱(廠蓋鬱窪鹽鹹鏇鬱夢製) = PF-04136309 500 mg BID 鏇艱艱繭淵製餘餘網鑰 (鑰鑰鬱襯構廠積範積築 ) 更多 | 不佳 | 2020-06-01 | |||
临床1期 | 转移性胰腺腺癌 一线 | 21 | (all pts) | 鑰壓築夢鑰齋醖膚鹹簾(積鏇繭鹹簾廠繭遞壓窪) = 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) 淵鹹廠鏇蓋遞艱襯淵壓 (築鏇鹽齋範鏇鑰鬱選鬱 ) 更多 | 积极 | 2017-09-09 |
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