Phase Ib Study of Ulixertinib Plus Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Adenocarcinoma.
Phase Ib Study of Ulixertinib Plus Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Adenocarcinoma.
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DOI：
10.1093/oncolo/oyac237
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发表时间：
2023-02-08
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影响因子：
--
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Ulixertinib是一种新型口服ERK抑制剂，在包括ras突变癌症患者的I期临床试验中显示出有希望的单药活性。我们进行了一项Ib期试验，联合乌利昔替尼、吉西他滨和nab-紫杉醇（GnP）治疗未经治疗的转移性胰腺腺癌。该试验包括剂量递减部分和推荐II期剂量（RP2D）的队列扩展部分。主要终点是确定乌利昔替尼加GnP的RP2D，次要终点是评估毒性和安全性，生化和放射学反应，无进展生存期（PFS）和总生存期（OS）。18名患者入组。最初给予乌利昔替尼600 mg PO，每日2次（BID），含GnP，但由于耐受性差，在剂量扩大初期将剂量降至450 mg BID作为RP2D，最终导致研究过早终止。常见的治疗相关不良事件（TRAEs）是贫血、血小板减少、皮疹和腹泻。在5例可评估反应的患者中，1例患者达到部分反应，2例患者达到病情稳定。对于接受三胞胎的15例患者，中位PFS和OS分别为5.46和12.23个月。乌利昔替尼加GnP具有与GnP相似的≥3级TRAEs发生率和潜在疗效，但全级别TRAEs发生率较高（ClinicalTrials.gov识别码：NCT02608229）。Ulixertinib在包括ras突变癌症患者的I期临床试验中显示出有希望的单药活性。该Ib期试验联合乌利昔替尼、吉西他滨和nab-紫杉醇治疗未经治疗的转移性胰腺腺癌。结果报告在这里。
Ulixertinib is a novel oral ERK inhibitor that has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers. We conducted a phase Ib trial combining ulixertinib with gemcitabine and nab-paclitaxel (GnP) for untreated metastatic pancreatic adenocarcinoma. The trial comprised a dose de-escalation part and a cohort expansion part at the recommended phase II dose (RP2D). Primary endpoint was to determine the RP2D of ulixertinib plus GnP and secondary endpoints were to assess toxicity and safety profile, biochemical and radiographic response, progression-free survival (PFS) and overall survival (OS). Eighteen patients were enrolled. Ulixertinib 600 mg PO twice daily (BID) with GnP was initially administered but was de-escalated to 450 mg BID as RP2D early during dose expansion due to poor tolerability, which ultimately led to premature termination of the study. Common treatment-related adverse events (TRAEs) were anemia, thrombocytopenia, rash and diarrhea. For 5 response evaluable patients, one patient achieved a partial response and 2 patients achieved stable disease. For 15 patients who received the triplet, median PFS and OS were 5.46 and 12.23 months, respectively. Ulixertinib plus GnP had similar frequency of grade ≥3 TRAEs and potentially efficacy as GnP, however was complicated by a high rate of all-grade TRAEs (ClinicalTrials.gov Identifier: NCT02608229). Ulixertinib has shown promising single-agent activity in a phase I clinical trial that included patients with RAS-mutant cancers. This phase Ib trial combined ulixertinib with gemcitabine and nab-paclitaxel for untreated metastatic pancreatic adenocarcinoma. Results are reported here.
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影响因子：
50.3
作者：
Singh A;Greninger P;Rhodes D;Koopman L;Violette S;Bardeesy N;Settleman J
通讯作者：
Settleman J
影响因子：
4.5
作者：
Cascinu, Stefano;Berardi, Rossana;Cinquini, Michela
通讯作者：
Cinquini, Michela
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
DOI：
10.1038/nrc2960
发表时间：
2010-12
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-14-1051
发表时间：
2015-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Whatcott CJ;Diep CH;Jiang P;Watanabe A;LoBello J;Sima C;Hostetter G;Shepard HM;Von Hoff DD;Han H
通讯作者：
Han H