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Leora Horn, Jeffrey R Infante, Karen L Reckamp, George R Blumenshein, Ticiana A Leal, Saiama N Waqar, Barbara J Gitlitz, Rachel E Sanborn, Jennifer G Whisenant, Liping Du, Joel W Neal, Jon P Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J Gibbons, Allison Holzhausen, Christine M Lovly, Heather A Wakelee
PURPOSE: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: In dose escalation, ensartinib was administered at doses of 25-250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily...
March 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Eric K Singhi, Leora Horn
Despite significant advancements in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) since the advent of crizotinib, the development of acquired resistance and poor CNS efficacy have necessitated the search for novel and more robust therapies. Ensartinib (X-396) is a novel second-generation ALK-tyrosine kinase inhibitor (TKI) that holds much clinical promise. Preclinical data have demonstrated increased potency of the drug as compared with crizotinib and other second-generation ALK-TKI therapies such as alectinib and ceritinib...
March 6, 2018: Future Oncology
Tony S K Mok, Lucio Crino, Enriqueta Felip, Ravi Salgia, Tommaso De Pas, Daniel S W Tan, Laura Q M Chow
The discovery of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved-ceritinib and alectinib-and others that are in development-brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms...
April 2017: Cancer Treatment Reviews
Leora Horn, Heather Wakelee, Karen L Reckamp, George Blumenschein, Jeffrey R Infante, Corey A Carter, Saiama N Waqar, Joel W Neal, Kimberly Harrow, Jon P Gockerman, Gary Dukart, Chris Liang, James L Gibbons, Jennifer Hernandez, Tera Newman-Eerkes, Lee Lim, Christine M Lovly
No abstract text is available yet for this article.
November 2016: Journal of Thoracic Oncology
Ticiana Leal, Heather Wakelee, Jeffrey Infante, George Blumenschein, Karen Reckamp, Corey Carter, Saiama Waqar, Jon Gockerman, Christine Lovly, Gary Dukart, Kimberly Harrow, Chris Liang, James Gibbons, Leora Horn
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Oncology
Ticiana Leal, Heather Wakelee, Jeffrey Infante, George Blumenschein, Karen Reckamp, Corey Carter, Saiama Waqar, Jon Gockerman, Christine Lovly, Gary Dukart, Kimberly Harrow, Chris Liang, James Gibbons, Leora Horn
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Oncology
Wade T Iams, Christine M Lovly
The therapeutic targeting of anaplastic lymphoma kinase (ALK) has been a burgeoning area of research since 2007 when ALK fusions were initially identified in patients with non-small cell lung cancer. The field has rapidly progressed through development of the first-generation ALK inhibitor, crizotinib, to an understanding of mechanisms of acquired resistance to crizotinib and is currently witnessing an explosion in the development of next-generation ALK inhibitors such as ceritinib, alectinib, PF-06463922, AP26113, X-396, and TSR-011...
September 2015: Cancer Journal
Daniela Di Paolo, D Yang, Fabio Pastorino, Laura Emionite, Michele Cilli, Antonio Daga, Elisa Destafanis, Annarita Di Fiore, Francesca Piaggio, Chiara Brignole, Xiaobao Xu, Chris Liang, James Gibbons, Mirco Ponzoni, Patrizia Perri
Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models...
October 6, 2015: Oncotarget
Georg Pall
PURPOSE OF REVIEW: Crizotinib now is accepted as the standard first-line treatment of ALK-rearranged lung adenocarcinomas. To overcome the problem of crizotinib resistance, second-generation ALK inhibitors are in development. The aim of this review is to give an overview on the mechanisms behind crizotinib resistance and on the preclinical background and clinical development of these compounds. RECENT FINDINGS: Based on phase I/II data, ceritinib has gained accelerated FDA approval for the treatment of crizotinib-resistant ALK-rearranged lung cancer...
March 2015: Current Opinion in Oncology
Mark M Awad, Alice T Shaw
The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440...
July 2014: Clinical Advances in Hematology & Oncology: H&O
Christine M Lovly, Johannes M Heuckmann, Elisa de Stanchina, Heidi Chen, Roman K Thomas, Chris Liang, William Pao
Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials...
July 15, 2011: Cancer Research
Indrek Tulp, Dimitar A Dobchev, Alan R Katritzky, William Acree, Uko Maran
Principal component analysis (PCA) of a large data matrix (153 solvents x 396 solutes) for Ostwald solubility coefficients (log L) resulted in a two-component model covering 98.6% of the variability. Analysis of the principal components exposed the structural characteristics of solutes and solvents that codify interactions which determine the behavior of a chemical in the surrounding media. The pattern revealed by PCA analysis distinguishes solutes according to the molecular size, functional groups, and electrostatic interactions, such as polarity and hydrogen-bonding donor and acceptor properties...
July 26, 2010: Journal of Chemical Information and Modeling
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