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https://www.readbyqxmd.com/read/28719152/a-first-in-human-phase-i-multicenter-open-label-dose-escalation-study-of-the-oral-raf-vegfr-2-inhibitor-raf265-in-locally-advanced-or-metastatic-melanoma-independent-from-braf-mutation-status
#1
Benjamin Izar, William Sharfman, F Stephen Hodi, Donald Lawrence, Keith T Flaherty, Ravi Amaravadi, Kevin B Kim, Igor Puzanov, Jeffrey Sosman, Reinhard Dummer, Simone M Goldinger, Lyhping Lam, Shefali Kakar, Zhongwen Tang, Oliver Krieter, David F McDermott, Michael B Atkins
To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]-fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis...
July 18, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28716404/partial-jejunal-diversion-using-an-incisionless-magnetic-anastomosis-system-1-year-interim-results-in-subjects-with-obesity-and-diabetes
#2
Evžen Machytka, Marek Bužga, Pavel Zonca, David B Lautz, Marvin Ryou, Donald C Simonson, Christopher C Thompson
BACKGROUND AND AIMS: The majority of patients with type 2 diabetes mellitus (T2DM) have obesity. Studies show that bariatric surgery is superior to medical treatment for remission of T2DM. Nevertheless, very few patients undergo surgery, and a less-invasive endoscopic alternative is desirable. METHODS: This was a single-arm first-in-human pilot study, designed to evaluate the technical feasibility, safety, and clinical performance of the incisionless magnetic anastomosis system (IMAS) in creation of a partial jejunal diversion (PJD)...
July 14, 2017: Gastrointestinal Endoscopy
https://www.readbyqxmd.com/read/28715648/tumor-suppressor-candidate-2-tusc2-fus-1-and-human-cancers
#3
Tadas Rimkus, Sherona Sirkisoon, Alexandra Harrison, Hui-Wen Lo
Tumor suppressor candidate 2 (TUSC2, also known as FUS1) was identified in 2000 as a candidate tumor suppressor gene located in a region on chromosome 3p21.3 that is homozygously deleted in some lung and breast cancers. The deletion is rare in lung and breast cancers, but is frequent in malignant pleural mesothelioma. Evidence to date indicates that TUSC2 behaves as a tumor suppressor in lung cancer; however, its role as a tumor suppressor for other tumor types has not been fully established. Loss of TUSC2 expression at the mRNA and protein levels has been reported in various cancers...
May 2017: Discovery Medicine
https://www.readbyqxmd.com/read/28707423/a-universal-drug-delivery-catheter-for-the-treatment-of-infrapopliteal-arterial-disease-results-from-the-multi-center-first-in-human-study
#4
Frank Bunch, Craig Walker, Elias Kassab, Jeffrey Carr
OBJECTIVE: The objective of this study was to assess the feasibility, safety and initial efficacy of paclitaxel administration using a novel drug delivery catheter for the prevention of restenosis in infrapopliteal de novo and restenotic lesions. BACKGROUND: Restenosis continues to be a great challenge after percutaneous revascularization procedures for peripheral arterial disease, particularly for below-the-knee applications. METHODS: A prospective, multicenter first-in-human registry of a novel delivery catheter delivering liquid paclitaxel was conducted in 10 patients...
July 14, 2017: Catheterization and Cardiovascular Interventions
https://www.readbyqxmd.com/read/28705916/biodistribution-and-dosimetry-of-18-f-meta-fluorobenzyl-guanidine-mfbg-a-first-in-human-pet-ct-imaging-study-of-patients-with-neuroendocrine-malignancies
#5
Neeta Pandit-Taskar, Pat B Zanzonico, Kevin D Staton, Jorge A Carrasquillo, Diane Reidy-Lagunes, Serge K Lyashchenko, Eva Burnazi, Hanwen Zhang, Jason S Lewis, Ronald Blasberg, Steven M Larson, Wolfgang Andreas Weber, Shakeel Modak
Introduction: Iodine-123-meta-iodobenzylguanidine ((123)I-MIBG) imaging is currently a mainstay in the evaluation of many neuroendocrine tumors, especially neuroblastoma. (123)I-MIBG imaging has several limitations that can be overcome by the use of a PET agent. (18)F-MFBG is a positron emission tomography (PET) analog of MIBG that may allow for single-day, high-resolution quantitative imaging. We conducted a first-in-human study of (18)F-MFBG PET imaging to evaluate the safety, feasibility, pharmacokinetics, and dosimetry of (18)F-MFBG in neuroendocrine tumors (NETs)...
July 13, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28699134/intraoperative-tumor-detection-using-a-ratiometric-activatable-fluorescent-peptide-a-first-in-human-phase-1-study
#6
Jonathan T Unkart, Steven L Chen, Irene L Wapnir, Jesús E González, Alec Harootunian, Anne M Wallace
BACKGROUND: Positive surgical margins remain a significant challenge in breast cancer surgery. This report describes the use of a novel, first-in-human ratiometric activatable cell-penetrating peptide in breast cancer surgery. METHODS: A two-part, multi-institutional phase 1 trial of AVB-620 with a 3+3 dose escalation and dose-expansion cohorts was conducted. The patients received an infusion of AVB-620 2-20 h before planned lumpectomy/mastectomy and sentinel node biopsy/axillary dissection...
July 11, 2017: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/28696690/a-kinome-wide-selective-radiolabeled-trkb-c-inhibitor-for-in-vitro-and-in-vivo-neuroimaging-synthesis-preclinical-evaluation-and-first-in-human
#7
Vadim Bernard-Gauthier, Justin J Bailey, Andrew V Mossine, Simon Klaus Lindner, Lena Vomacka, Arturo Aliaga, Xia Shao, Carole A Quesada, Phillip S Sherman, Anne Mahringer, Alexey Kostikov, Marilyn Grand'Maison, Pedro Rosa-Neto, Jean-Paul Soucy, Alexander Thiel, David R Kaplan, Gert Fricker, Björn Wängler, Peter Bartenstein, Ralf Schirrmacher, Peter J H Scott
The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [(11)C]-(R)-3 ([(11)C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [(11)C]-(R)-3 readily crosses the blood-brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies...
July 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28692182/gsk2878175-a-pan-genotypic-non-nucleoside-ns5b-polymerase-inhibitor-in-healthy-and-treatment-na%C3%A3-ve-chronic-hepatitis-c-subjects
#8
Stephen D Gardner, Joseph Kim, Sharon Baptiste-Brown, Vincent Lopez, Robert Hamatake, Jianjun Gan, Stephen Edwards, Lucinda Elko-Simms, Etienne F Dumont, Martin Leivers, Zhi Hong, Melanie T Paff
GSK2878175 is a potent, pan-genotypic, non-nucleoside, non-structural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first-in-human, randomized, placebo-controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof-of-concept, placebo-controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics, and antiviral activity of GSK2878175 monotherapy in treatment naïve, non-cirrhotic, subjects with HCV genotype 1 [1a and 1b], 2, or 3...
July 10, 2017: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/28689370/intra-target-microdosing-a-novel-drug-development-approach-proof-of-concept-safety-and-feasibility-study-in-humans
#9
T Burt, D MacLeod, K Lee, A Santoro, D K DeMasi, T Hawk, M Feinglos, M Rowland, R J Noveck
Intra-target microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits...
July 8, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28689115/liposomal-honokiol-induced-lysosomal-degradation-of-hsp90-client-proteins-and-protective-autophagy-in-both-gefitinib-sensitive-and-gefitinib-resistant-nsclc-cells
#10
Jianhong Yang, Wenshuang Wu, Jiaolin Wen, Haoyu Ye, Hong Luo, Peng Bai, Minghai Tang, Fang Wang, Li Zheng, Shengyong Yang, Weimin Li, Aihua Peng, Li Yang, Li Wan, Lijuan Chen
Honokiol (HK), a natural chemical isolated from Mangnolia officinalis, has shown antitumorigenic activities when used to treat a variety of tumor cell lines. The mechanism of honokiol activity when used to treat gefitinib-sensitive and gefitinib-resistant non-small cell lung cancer (NSCLC) requires elucidation. Here, the presence of liposomal honokiol (LHK) induced apoptotic and antitumor activities in four xenograft models generated using NSCLC cell lines such as HCC827 (gefitinib-sensitive) and H1975 (gefitinib-resistant)...
July 4, 2017: Biomaterials
https://www.readbyqxmd.com/read/28681444/a-call-to-incorporate-systems-theory-and-human-factors-into-the-existing-investigation-of-harm-in-clinical-research-involving-healthcare-products
#11
Bernard Bégaud, Esther Daemen, Ioannis Dokas, Brian Edwards, Jonathan M Fishbein, Howard E Greenberg, Alan Hochberg, Hervé Le Louet, Jytte Lyngvig, Nataliya Mogles, Kathryn Owen, Christine Prendergast, Martin Rejzek, Sofia Trantza, David Webb, Matthew Whalen, Simon Whiteley
This is a joint statement from individual pharmacology and pharmaceutical professionals acting in their own capacity including members of the Alliance for Clinical Research Excellence and Safety (ACRES) and the International Society of Pharmacovigilance (ISoP). By building on the extensive pharmacological and regulatory investigations that already take place, we are calling for a fuller and more robust systems-based approach to the independent investigation of clinical research when serious incidents of harm occur, starting with first-in-human clinical trials...
July 6, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28678784/personalized-rna-mutanome-vaccines-mobilize-poly-specific-therapeutic-immunity-against-cancer
#12
Ugur Sahin, Evelyna Derhovanessian, Matthias Miller, Björn-Philipp Kloke, Petra Simon, Martin Löwer, Valesca Bukur, Arbel D Tadmor, Ulrich Luxemburger, Barbara Schrörs, Tana Omokoko, Mathias Vormehr, Christian Albrecht, Anna Paruzynski, Andreas N Kuhn, Janina Buck, Sandra Heesch, Katharina H Schreeb, Felicitas Müller, Inga Ortseifer, Isabel Vogler, Eva Godehardt, Sebastian Attig, Richard Rae, Andrea Breitkreuz, Claudia Tolliver, Martin Suchan, Goran Martic, Alexander Hohberger, Patrick Sorn, Jan Diekmann, Janko Ciesla, Olga Waksmann, Alexandra-Kemmer Brück, Meike Witt, Martina Zillgen, Andree Rothermel, Barbara Kasemann, David Langer, Stefanie Bolte, Mustafa Diken, Sebastian Kreiter, Romina Nemecek, Christoffer Gebhardt, Stephan Grabbe, Christoph Höller, Jochen Utikal, Christoph Huber, Carmen Loquai, Özlem Türeci
T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient...
July 13, 2017: Nature
https://www.readbyqxmd.com/read/28673774/development-functional-characterization-and-validation-of-methodology-for-gmp-compliant-manufacture-of-phagocytic-macrophages-a-novel-cellular-therapeutic-for-liver-cirrhosis
#13
Alasdair R Fraser, Chloe Pass, Paul Burgoyne, Anne Atkinson, Laura Bailey, Audrey Laurie, Neil W A McGowan, Akib Hamid, Joanna K Moore, Benjamin J Dwyer, Marc L Turner, Stuart J Forbes, John D M Campbell
BACKGROUND AIMS: Autologous macrophage therapy represents a potentially significant therapeutic advance for the treatment of severe progressive liver cirrhosis. Administration of macrophages has been shown to reduce inflammation and drive fibrotic scar breakdown and tissue repair in relevant models. This therapeutic approach is being assessed for safety and feasibility in a first-in-human trial (MAcrophages Therapy for liver CirrHosis [MATCH] trial). METHODS: We outline the development and validation phases of GMP production...
June 30, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28660432/human-microdosing-and-mice-xenograft-data-of-agm-130-applied-to-estimate-efficacious-doses-in-patients
#14
Wan-Su Park, Gab-Jin Park, Seunghoon Han, Sooho Ban, Moon-Young Park, San-Ho Kim, Seon-Myung Kim, Yong-Chul Kim, Hyung Sik Kim, Young G Shin, Dong-Seok Yim
PURPOSE: AGM-130 is a cyclin-dependent kinase inhibitor that exhibits dose-dependent efficacy in xenograft mouse models. During preclinical pharmacokinetic (PK) studies, mice and rats showed comparable PK parameters while dogs showed unusually high clearance (CL), which has made human PK prediction challenging. To address this discrepancy, we performed a human microdosing PK and developed a mouse PK/PD model in order to guide the first-in-human studies. METHODS: A microdose of AGM-130 was given via intravenous injection to healthy subjects...
June 28, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28655795/first-in-human-study-of-amg%C3%A2-820-a-monoclonal-anti-colony-stimulating-factor-1-receptor-antibody-in-patients-with-advanced-solid-tumors
#15
Kyriakos P Papadopoulos, Larry Gluck, Lainie P Martin, Anthony J Olszanski, Anthony W Tolcher, Gataree Ngarmchamnanrith, Erik Rasmussen, Benny Amore, Dirk Nagorsen, John S Hill, Joe Stephenson
Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and interleukin-34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820.<br /><br />Experimental Design: Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0...
June 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28645776/selective-inhibition-of-flt3-by-gilteritinib-in-relapsed-or-refractory-acute-myeloid-leukaemia-a-multicentre-first-in-human-open-label-phase-1-2-study
#16
Alexander E Perl, Jessica K Altman, Jorge Cortes, Catherine Smith, Mark Litzow, Maria R Baer, David Claxton, Harry P Erba, Stan Gill, Stuart Goldberg, Joseph G Jurcic, Richard A Larson, Chaofeng Liu, Ellen Ritchie, Gary Schiller, Alexander I Spira, Stephen A Strickland, Raoul Tibes, Celalettin Ustun, Eunice S Wang, Robert Stuart, Christoph Röllig, Andreas Neubauer, Giovanni Martinelli, Erkut Bahceci, Mark Levis
BACKGROUND: Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment...
June 20, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28642820/intratumorally-injected-pro-inflammatory-allogeneic-dendritic-cells-as-immune-enhancers-a-first-in-human-study-in-unfavourable-risk-patients-with-metastatic-renal-cell-carcinoma
#17
Anna Laurell, Maria Lönnemark, Einar Brekkan, Anders Magnusson, Anna Tolf, Anna Carin Wallgren, Bengt Andersson, Lars Adamson, Rolf Kiessling, Alex Karlsson-Parra
BACKGROUND: Accumulating pre-clinical data indicate that the efficient induction of antigen-specific cytotoxic CD8+ T cells characterizing viral infections is caused by cross-priming where initially infected DCs produce an unique set of inflammatory factors that recruit and activate non-infected bystander DCs. Our DC-based immunotherapy concept is guided by such bystander view and accordingly, we have developed a cellular adjuvant consisting of pre-activated allogeneic DCs producing high levels of DC-recruiting and DC-activating factors...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28641925/safety-pharmacokinetics-and-sialic-acid-production-after-oral-administration-of-n-acetylmannosamine-mannac-to-subjects-with-gne-myopathy
#18
Xin Xu, Amy Q Wang, Lea L Latham, Frank Celeste, Carla Ciccone, May Christine Malicdan, Barry Goldspiel, Pramod Terse, James Cradock, Nora Yang, Selwyn Yorke, John C McKew, William A Gahl, Marjan Huizing, Nuria Carrillo
GNE myopathy is a rare, autosomal recessive, inborn error of sialic acid metabolism, caused by mutations in GNE, the gene encoding UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase. The disease manifests as an adult-onset myopathy characterized by progressive skeletal muscle weakness and atrophy. There is no medical therapy available for this debilitating disease. Hyposialylation of muscle glycoproteins likely contributes to the pathophysiology of this disease. N-acetyl-D-mannosamine (ManNAc), an uncharged monosaccharide and the first committed precursor in the sialic acid biosynthetic pathway, is a therapeutic candidate that prevents muscle weakness in the mouse model of GNE myopathy...
April 26, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28639118/pharmacokinetics-and-immunogenicity-of-t0001-a-newly-developed-anti-tnf%C3%AE-fusion-protein-in-healthy-volunteers
#19
Yitong Wang, Chang Liu, Shi Chen, Wei Wang, Lihou Dong, Qian Wang, Yan Wang, Libo Zhao, Yannan Zang, Zhenwei Xie, Yang Liu, Yanjun Liu, Haifeng Song, Zhanguo Li, Yi Fang
PURPOSE: T0001 was the first mutant of recombinant fusion protein of human tumor necrosis factor receptor and Fc fragment (rhTNFR:Fc) based on etanercept on a global scale. This study was carried out to investigate the pharmacokinetics (PK) and immunogenicity of T0001 in healthy Chinese volunteers. METHODS: This study was randomized, with a single ascending dose, and the first-in-human clinical trial of T0001. Healthy Chinese volunteers (n = 56; male: female = 1:1) were randomly assigned to receive a single subcutaneous (sc) injection of 10, 20, 35, 50, 65 or 75 mg of T0001...
June 21, 2017: European Journal of Clinical Pharmacology
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
#20
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
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