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FGFR inhibitors toxicity

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https://www.readbyqxmd.com/read/28728751/a-phase-ii-evaluation-of-brivanib-in-the-treatment-of-persistent-or-recurrent-carcinoma-of-the-cervix-an-nrg-oncology-gynecologic-oncology-group-study
#1
John K Chan, Wei Deng, Robert V Higgins, Krishnansu S Tewari, Albert J Bonebrake, Michael Hicks, Stephanie Gaillard, Pedro T Ramirez, Weldon Chafe, Bradley J Monk, Carol Aghajanian
BACKGROUND: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. METHODS: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity...
September 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28721753/nintedanib-in-ovarian-cancer
#2
REVIEW
Saira Khalique, Susana Banerjee
Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and β, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far...
September 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28624695/first-in-human-phase-i-study-of-oral-s49076-a-unique-met-axl-fgfr-inhibitor-in-advanced-solid-tumours
#3
MULTICENTER STUDY
Jordi Rodon, Sophie Postel-Vinay, Antoine Hollebecque, Paolo Nuciforo, Analia Azaro, Valérie Cattan, Lucie Marfai, Isabelle Sudey, Karl Brendel, Audrey Delmas, Stéphanie Malasse, Jean-Charles Soria
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD...
August 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28589492/a-phase-1-study-of-ly2874455-an-oral-selective-pan-fgfr-inhibitor-in-patients-with-advanced-cancer
#4
Michael Michael, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, Tae Min Kim, Oday Hamid, Donald Thornton, Sonya C Tate, Eyas Raddad, Jeanne Tie
BACKGROUND: We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor. OBJECTIVE: The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455. PATIENTS AND METHODS: This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC)...
August 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28377480/a-phase-ii-study-of-dovitinib-in-patients-with-recurrent-or-metastatic-adenoid-cystic-carcinoma
#5
Patrick M Dillon, Gina R Petroni, Bethany J Horton, Christopher A Moskaluk, Paula M Fracasso, Michael G Douvas, Nikole Varhegyi, Snjezana Zaja-Milatovic, Christopher Y Thomas
Purpose: Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC.Experimental Design: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28161661/multi-chemotherapeutic-schedules-containing-the-pan-fgfr-inhibitor-arq-087-are-safe-and-show-antitumor-activity-in-different-xenograft-models
#6
Rosaria Chilà, Terence Hall G, Giovanni Abbadessa, Massimo Broggini, Giovanna Damia
ARQ 087 is a multi-tyrosine kinase inhibitor with potent activity against the FGFR receptor family, currently in Phase I clinical studies for the treatment of advanced solid tumors. The compound has a very safe profile and induces tumor regressions in FGFR-driven models. The feasibility of combining ARQ 087 with chemotherapy was investigated in FGFR deregulated human xenografts. Nude mice were transplanted subcutaneously with H1581, and when tumor masses reached 150 mg, were randomized to receive vehicle, ARQ 087, paclitaxel, carboplatin as single agents or in combination...
April 2017: Translational Oncology
https://www.readbyqxmd.com/read/28121208/fgfr-targeted-therapeutics-for-the-treatment-of-breast-cancer
#7
REVIEW
Antonella De Luca, Daniela Frezzetti, Marianna Gallo, Nicola Normanno
Breast cancer is a complex disease and several molecular drivers regulate its progression. Fibroblast growth factor receptor (FGFR) signaling is frequently deregulated in many cancers, including breast cancer. Due the involvement of the FGFR/FGF axis in the pathogenesis and progression of tumors, FGFR-targeted agents might represent a potential therapeutic option for breast cancer patients. Areas covered: This review offers an overview of targeted agents against FGFRs and their clinical development in breast cancer...
March 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28117910/oligodendroglial-fibroblast-growth-factor-receptor-1-gene-targeting-protects-mice-from-experimental-autoimmune-encephalomyelitis-through-erk-akt-phosphorylation
#8
Ranjithkumar Rajendran, Mario Giraldo Velásquez, Christine Stadelmann, Martin Berghoff
Fibroblast growth factors (FGFs) exert diverse biological effects by binding and activation of specific fibroblast growth factor receptors (FGFRs). FGFs and FGFRs have been implicated in demyelinating pathologies including multiple sclerosis. In vitro activation of the FGF2/FGFR1 pathway results in downregulation of myelin proteins. FGF1, 2 and 9 have been shown to be involved in the pathology of multiple sclerosis. Recent studies on the function of oligodendroglial FGFR1 in a model of toxic demyelination showed that deletion of FGFR1 led to increased remyelination and preservation of axonal density and an increased number of mature oligodendrocytes...
January 24, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28070720/safety-tolerability-and-pharmacokinetics-of-the-fibroblast-growth-factor-receptor-inhibitor-azd4547-in-japanese-patients-with-advanced-solid-tumours-a-phase-i-study
#9
Hideo Saka, Chiyoe Kitagawa, Yoshihito Kogure, Yasuo Takahashi, Koshi Fujikawa, Tamotsu Sagawa, Satoru Iwasa, Naoki Takahashi, Taro Fukao, Catherine Tchinou, Dónal Landers, Yasuhide Yamada
Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization...
August 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28030802/inhibition-of-the-fibroblast-growth-factor-receptor-fgfr-pathway-the-current-landscape-and-barriers-to-clinical-application
#10
REVIEW
Young Kwang Chae, Keerthi Ranganath, Peter S Hammerman, Christos Vaklavas, Nisha Mohindra, Aparna Kalyan, Maria Matsangou, Ricardo Costa, Benedito Carneiro, Victoria M Villaflor, Massimo Cristofanilli, Francis J Giles
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis...
February 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/27870574/evaluation-of-bgj398-a-fibroblast-growth-factor-receptor-1-3-kinase-inhibitor-in-patients-with-advanced-solid-tumors-harboring-genetic-alterations-in-fibroblast-growth-factor-receptors-results-of-a-global-phase-i-dose-escalation-and-dose-expansion-study
#11
Lucia Nogova, Lecia V Sequist, Jose Manuel Perez Garcia, Fabrice Andre, Jean-Pierre Delord, Manuel Hidalgo, Jan H M Schellens, Philippe A Cassier, D Ross Camidge, Martin Schuler, Ulka Vaishampayan, Howard Burris, G Gary Tian, Mario Campone, Zev A Wainberg, Wan-Teck Lim, Patricia LoRusso, Geoffrey I Shapiro, Katie Parker, Xueying Chen, Somesh Choudhury, Francois Ringeisen, Diana Graus-Porta, Dale Porter, Randi Isaacs, Reinhard Buettner, Jürgen Wolf
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27716819/a-phase-i-dose-escalation-study-of-the-triple-angiokinase-inhibitor-nintedanib-combined-with-low-dose-cytarabine-in-elderly-patients-with-acute-myeloid-leukemia
#12
Christoph Schliemann, Joachim Gerss, Stefanie Wiebe, Jan-Henrik Mikesch, Nicola Knoblauch, Tim Sauer, Linus Angenendt, Tobias Kewitz, Marc Urban, Trude Butterfass-Bahloul, Sabine Edemir, Kerstin Vehring, Carsten Müller-Tidow, Wolfgang E Berdel, Utz Krug
Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles...
2016: PloS One
https://www.readbyqxmd.com/read/27315356/efficacy-and-safety-of-dovitinib-in-pretreated-patients-with-advanced-squamous-non-small-cell-lung-cancer-with-fgfr1-amplification-a-single-arm-phase-2-study
#13
Sung Hee Lim, Jong-Mu Sun, Yoon-La Choi, Hye Ryun Kim, Soomin Ahn, Ji Yun Lee, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Joo Hang Kim, Byoung Chul Cho, Myung-Ju Ahn
BACKGROUND: Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung. METHODS: Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled. Dovitinib at a dose of 500 mg was administered orally, once daily, on days 1 to 5 of every week, followed by 2 days off...
October 2016: Cancer
https://www.readbyqxmd.com/read/27100354/phase-i-trial-of-dovitinib-tki258-in-recurrent-glioblastoma
#14
Niklas Schäfer, Gerrit H Gielen, Sied Kebir, Anja Wieland, Andreas Till, Frederic Mack, Christina Schaub, Theophilos Tzaridis, Roman Reinartz, Michael Niessen, Rolf Fimmers, Matthias Simon, Christoph Coch, Christine Fuhrmann, Ulrich Herrlinger, Björn Scheffler, Martin Glas
PURPOSE: Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR β, and c-Kit. Since dovitinib is able to cross the blood-brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM). PATIENTS AND METHODS: Patients with first or second GBM recurrence started treatment with the maximal tolerated dose (MTD) previously established in systemic cancer patients (500 mg/d, 5 days on/2 days off)...
July 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/26579384/pd173074-a-selective-fgfr-inhibitor-reverses-mrp7-abcc10-mediated-mdr
#15
Nagaraju Anreddy, Atish Patel, Kamlesh Sodani, Rishil J Kathawala, Eugenie P Chen, John N D Wurpel, Zhe-Sheng Chen
Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7(-/-) mouse model compared to their wild-type counterparts...
June 2014: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/26536461/pleiotropic-anti-angiogenic-and-anti-oncogenic-activities-of-the-novel-mithralog-demycarosyl-3d-%C3%A3-d-digitoxosyl-mithramycin-sk-ec-8042
#16
Azahara Fernández-Guizán, Alejandro López-Soto, Andrea Acebes-Huerta, Leticia Huergo-Zapico, Mónica Villa-Álvarez, Luz-Elena Núñez, Francisco Morís, Segundo Gonzalez
Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA...
2015: PloS One
https://www.readbyqxmd.com/read/26494904/multikinase-activity-of-fibroblast-growth-factor-receptor-fgfr-inhibitors-su5402-pd173074-azd1480-azd4547-and-bgj398-compromises-the-use-of-small-chemicals-targeting-fgfr-catalytic-activity-for-therapy-of-short-stature-syndromes
#17
Iva Gudernova, Iva Vesela, Lukas Balek, Marcela Buchtova, Hana Dosedelova, Michaela Kunova, Jakub Pivnicka, Iva Jelinkova, Lucie Roubalova, Alois Kozubik, Pavel Krejci
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation...
January 1, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/26424114/fgf9-induced-changes-in-cellular-redox-status-and-ho-1-upregulation-are-fgfr-dependent-and-proceed-through-both-erk-and-akt-to-induce-creb-and-nrf2-activation
#18
Jih-Ing Chuang, Jui-Yen Huang, Shaw-Jenq Tsai, H Sunny Sun, Shang-Hsun Yang, Pei-Chin Chuang, Bu-Miin Huang, Cheng-Hsin Ching
Our previous studies demonstrated that fibroblast growth factor 9 (FGF9) protects cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative insult by upregulation of γ-glutamylcysteine synthetase (γ-GCS) and heme oxygenase-1 (HO-1). However, the mechanisms responsible for FGF9-induced γ-GCS and HO-1 upregulation remain uncharacterized. In the present study, we demonstrate the signaling pathways by which FGF9 upregulates HO-1 and γ-GCS expression. We found that FGF9-induced HO-1 and γ-GCS expression was prevented by PD173014, an inhibitor of the FGF receptor (FGFR)...
December 2015: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/26324363/phase-i-dose-escalation-study-of-jnj-42756493-an-oral-pan-fibroblast-growth-factor-receptor-inhibitor-in-patients-with-advanced-solid-tumors
#19
MULTICENTER STUDY
Josep Tabernero, Rastislav Bahleda, Rodrigo Dienstmann, Jeffrey R Infante, Alain Mita, Antoine Italiano, Emiliano Calvo, Victor Moreno, Barbara Adamo, Anas Gazzah, Bob Zhong, Suso J Platero, Johan W Smit, Kim Stuyckens, Moitreyee Chatterjee-Kishore, Jordi Rodon, Vijay Peddareddigari, Feng R Luo, Jean-Charles Soria
PURPOSE: JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493. PATIENTS AND METHODS: Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently (7 days on/7 days off)...
October 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/26078430/targeting-fgfr-signaling-in-cancer
#20
REVIEW
Mehdi Touat, Ecaterina Ileana, Sophie Postel-Vinay, Fabrice André, Jean-Charles Soria
The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies...
June 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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