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First-in-human phase 1 study

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https://www.readbyqxmd.com/read/28109128/population-pharmacokinetics-and-pharmacodynamics-of-benralizumab-in-healthy-volunteers-and-patients-with-asthma
#1
B Wang, L Yan, Z Yao, L K Roskos
Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α, immunoglobulin G (IgG) 1 κ monoclonal antibody. We developed a population pharmacokinetic (PK)/pharmacodynamic (PD) model for benralizumab by analyzing PK and blood eosinophil count data from two healthy volunteer studies (N = 48) and four studies in patients with asthma (N = 152). Benralizumab PK was dose-proportional and adequately described by a two-compartment model with first-order elimination from the central compartment and first-order absorption from the subcutaneous dosing site...
January 21, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28107699/analysis-of-n-nitrosonornicotine-enantiomers-in-human-urine-by-chiral-stationary-phase-liquid-chromatography-nanoelectrospray-ionization-high-resolution-tandem-mass-spectrometry
#2
Jing Yang, Steven G Carmella, Stephen S Hecht
We have developed a chiral stationary phase liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry (LC-NSI-HRMS/MS) method to investigate the enantiomeric composition of low parts per trillion amounts of the carcinogen N'-nitrosonornicotine (NNN) in the urine of cigarette smokers and smokeless tobacco users. (S)-NNN is the major enantiomer in tobacco and is more carcinogenic than (R)-NNN in rats, but no data are available on the enantiomeric composition of NNN in humans. The method used [(13)C6]NNN as an internal standard and [pyridine-D4]nornicotine to monitor possible artifactual formation of NNN, which was found to be less than 2% of the quantified NNN...
January 9, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28107664/safety-and-efficacy-of-cardiopoietic-stem-cells-in-the-treatment-of-post-infarction-left-ventricular-dysfunction-from-cardioprotection-to-functional-repair-in-a-translational-pig-infarction-model
#3
Maximilian Y Emmert, Petra Wolint, Andras Jakab, Sean P Sheehy, Francesco S Pasqualini, Thi Dan Linh Nguyen, Monika Hilbe, Burkhardt Seifert, Benedikt Weber, Chad E Brokopp, Dominika Macejovska, Etem Caliskan, Arnold von Eckardstein, Ruth Schwartlander, Viola Vogel, Volkmar Falk, Kevin Kit Parker, Mariann Gyöngyösi, Simon P Hoerstrup
To date, clinical success of cardiac cell-therapies remains limited. To enhance the cardioreparative properties of stem cells, the concept of lineage-specification through cardiopoietic-guidance has been recently suggested. However, so far, only results from murine studies and from a clinical pilot-trial in chronic heart-failure (CHF) are available, while systematic evidence of its therapeutic-efficacy is still lacking. Importantly, also no data from large animals or for other indications are available. Therefore, we here investigate the therapeutic-efficacy of human cardiopoietic stem cells in the treatment of post-infarction LV-dysfunction using a translational pig-model...
November 23, 2016: Biomaterials
https://www.readbyqxmd.com/read/28105156/establishment-of-a-first-line-second-line-treatment-model-for-human-pulmonary-adenocarcinoma
#4
Lining Wang, Yu Wang, Qi Guan, Yong Liu, Tianyi He, Jiaru Wang
Lung cancer is one of the most prevalent types of cancer in the world. Surgery, chemotherapy and radiotherapy are used clinically as treatments for numerous cancers. Due to the appearance of drug resistance, the remission rate is limited to 40-50%. Docetaxel and pemetrexed are two drugs commonly used, and their effects in single-phase cell culture are well known. From the pharmacological point of view, it appears rational to hypothesize that sequential therapy effects can show better outcomes compared with traditional single-phase experiments...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28104787/binding-characteristics-of-galectin-3-fusion-proteins
#5
Sophia Böcker, Lothar Elling
Galectin-3 modulates cell adhesion and signaling events by specific binding and cross-linking galactoside containing carbohydrate ligands. Proteolytic cleavage by metalloproteinases yields in vivo N-terminally truncated galectin-3 still bearing the carbohydrate recognition domain. Truncated galectin-3 has been demonstrated to act in vivo as a negative inhibitor of galectin-3 due to higher affinity for carbohydrate ligands. We here present our studies on a series of twelve human galectin-3 protein constructs...
January 19, 2017: Glycobiology
https://www.readbyqxmd.com/read/28097385/two-phase-1-dose-escalation-studies-exploring-multiple-regimens-of-litronesib-ly2523355-an-eg5-inhibitor-in-patients-with-advanced-cancer
#6
Jeffrey R Infante, Amita Patnaik, Claire F Verschraegen, Anthony J Olszanski, Montaser Shaheen, Howard A Burris, Anthony W Tolcher, Kyriakos P Papadopoulos, Muralidhar Beeram, Scott M Hynes, Jennifer Leohr, Aimee Bence Lin, Lily Q Li, Anna McGlothlin, Daphne L Farrington, Eric H Westin, Roger B Cohen
PURPOSE: This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. METHODS: Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125-16 mg/m(2)/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1...
January 17, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28095146/phase-i-first-in-human-study-of-venetoclax-in-patients-with-relapsed-or-refractory-non-hodgkin-lymphoma
#7
Matthew S Davids, Andrew W Roberts, John F Seymour, John M Pagel, Brad S Kahl, William G Wierda, Soham Puvvada, Thomas J Kipps, Mary Ann Anderson, Ahmed Hamed Salem, Martin Dunbar, Ming Zhu, Franklin Peale, Jeremy A Ross, Lori Gressick, Monali Desai, Su Young Kim, Maria Verdugo, Rod A Humerickhouse, Gary B Gordon, John F Gerecitano
Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts...
January 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28093655/antibacterial-efficacy-and-cytotoxicity-of-low-intensity-direct-current-activated-silver-titanium-implant-system-prototype
#8
Zhuo Tan, Edward A Havell, Paul E Orndorff, Rohan A Shirwaiker
Silver-based devices activated by electric current are of interest in biomedicine because of their broad-spectrum antimicrobial activity. This study investigates the in vitro antibacterial efficacy and cytotoxicity of a low intensity direct current (LIDC)-activated silver-titanium implant system prototype designed for localized generation and delivery of silver ions at the implantation site. First, the antibacterial efficacy of the system was assessed against methicillin-resistant Staphylococcus aureus (MRSA) over 48 h at current levels of 3 and 6 µA in Mueller-Hinton broth...
January 16, 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/28093365/vitamin-b3-metal-organic-frameworks-as-potential-delivery-vehicles-for-therapeutic-nitric-oxide
#9
Rosana V Pinto, Fernando Antunes, João Pires, Vanessa Graça, Paula Brandão, Moisés L Pinto
: The synthesis and structural characterization of two isostructural metal (M=Ni, Co) 3D framework structure that integrate vitamin B3 building blocks with NO delivery capabilities and low toxicity is presented. The compounds with a formula [M2(μ2-H2O)(μ-vitamin B3)4]·2H2O contain two crystallographic distinct divalent metal centers connected by a bridging water and carboxylate group from vitamin B3. The porous compounds have the capability of storing and releasing nitric oxide (NO) in a slow and reversible manner, with released amounts of 2...
January 13, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28088839/pharmacokinetic-pharmacodynamic-modeling-of-the-pde4-inhibitor-tak-648-in-type-2-diabetes-early-translational-approaches-for-human-dose-prediction
#10
N Plock, S Vollert, M Mayer, G Hanauer, G Lahu
TAK-648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK-648 to required exposure in humans. A first-in-human study with single TAK-648 doses of 0...
January 15, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28074489/a-novel-nf-%C3%AE%C2%BAb-inhibitor-edasalonexent-cat-1004-in-development-as-a-disease-modifying-treatment-for-patients-with-duchenne-muscular-dystrophy-phase-1-safety-pharmacokinetics-and-pharmacodynamics-in-adult-subjects
#11
Joanne M Donovan, Michael Zimmer, Elliot Offman, Toni Grant, Michael Jirousek
In Duchenne muscular dystrophy (DMD), NF-κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT-1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF-κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF-κB upon intracellular cleavage to these bioactive components...
January 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28072927/artificial-induction-of-native-aquaporin-1-expression-in-human-salivary-cells
#12
Z Wang, S Pradhan-Bhatt, M C Farach-Carson, M J Passineau
Gene therapy for dry mouth disorders has transitioned in recent years from theoretical to clinical proof of principle with the publication of a first-in-man phase I/II dose escalation clinical trial in patients with radiation-induced xerostomia. This trial used a prototype adenoviral vector to express aquaporin-1 (AQP1), presumably in the ductal cell layer and/or in surviving acinar cells, to drive transcellular flux of interstitial fluid into the labyrinth of the salivary duct. As the development of this promising gene therapy continues, safety considerations are a high priority, particularly those that remove nonhuman agents (i...
January 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28070718/first-in-human-trial-of-an-anti-5t4-antibody-monomethylauristatin-conjugate-pf-06263507-in-patients-with-advanced-solid-tumors
#13
Geoffrey I Shapiro, Ulka N Vaishampayan, Patricia LoRusso, Jeremy Barton, Steven Hua, Steven D Reich, Ronald Shazer, Carrie T Taylor, Dawei Xuan, Hossein Borghaei
Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method...
January 9, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28063948/cytokine-il-10-activators-of-pi3-kinase-agonists-of-%C3%AE-2-adrenoreceptor-and-antioxidants-prevent-ischemia-induced-cell-death-in-rat-hippocampal-cultures
#14
Egor A Turovsky, Maria V Turovskaya, Sergei G Gaidin, Valery P Zinchenko
In the present work we compared the protective effect of anti-inflammatory cytokine IL-10 with the action of a PI3-kinase selective activator 740 Y-P, selective agonists of alpha-2 adrenoreceptor, guanfacine and UK-14,304, and compounds having antioxidant effect: recombinant human peroxiredoxin 6 and B27, in hippocampal cell culture during OGD (ischemia-like conditions). It has been shown that the response of cells to OGD in the control includes two phases. The first phase was accompanied by an increase in the frequency of spontaneous synchronous Ca(2+)-oscillations (SSCO) in neurons and Ca(2+)-pulse in astrocytes...
January 4, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28056400/efficacy-and-safety-of-eribulin-as-first-to-third-line-treatment-in-patients-with-advanced-or-metastatic-breast-cancer-previously-treated-with-anthracyclines-and-taxanes
#15
Shigeto Maeda, Michiyo Saimura, Shigeki Minami, Kaname Kurashita, Reiki Nishimura, Yuichiro Kai, Hiroshi Yano, Kohjiro Mashino, Shoshu Mitsuyama, Mototsugu Shimokawa, Kazuo Tamura
OBJECTIVES: Despite the survival benefit and acceptable tolerability of eribulin for advanced/metastatic breast cancer (MBC) patients pretreated with anthracyclines and taxanes, there is limited evidence of the clinical benefit of early eribulin use. We investigated the efficacy and safety of first- to third-line eribulin use in patients with MBC. MATERIALS AND METHODS: In this phase II, open-label, single-arm study conducted at 14 sites in Kyushu, Japan, women with histologically confirmed human epidermal growth factor receptor 2-negative MBC were enrolled between December 1, 2011 and November 30, 2013 (Data cut-off: November 30, 2014)...
January 2, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28056202/trastuzumab-emtansine-with-or-without-pertuzumab-versus-trastuzumab-plus-taxane-for-human-epidermal-growth-factor-receptor-2-positive-advanced-breast-cancer-primary-results-from-the-phase-iii-marianne-study
#16
Edith A Perez, Carlos Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pierfranco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier Pivot, Howard Burris, Jennifer A Petersen, Sven Stanzel, Alexander Strasak, Monika Patre, Paul Ellis
Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28054329/a-first-in-human-phase-1-study-of-epirubicin-conjugated-polymer-micelles-k-912-nc-6300-in-patients-with-advanced-or-recurrent-solid-tumors
#17
Hirofumi Mukai, Takahiro Kogawa, Nobuaki Matsubara, Yoichi Naito, Masaoki Sasaki, Ako Hosono
Background K-912 also known as NC-6300 is a novel epirubicin pro-drug conjugate developed using micellar nanoparticle technology. We conducted a first-in-human, Phase 1, open-label, non-randomized dose escalation study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of K-912 administered as monotherapy in patients with advanced or recurrent solid tumors. Methods Patients aged 41 to 72 years with histologically or cytologically confirmed advanced or recurrent malignant solid tumors either refractory to standard therapy or had no other viable treatment options were enrolled...
January 4, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28053021/first-in-human-phase-1-study-of-the-oral-inhibitor-of-indoleamine-2-3-dioxygenase-1-epacadostat-incb024360-in-patients-with-advanced-solid-malignancies
#18
Gregory L Beatty, Peter J O'Dwyer, Jason Clark, Jack G Shi, Kevin J Bowman, Peggy Scherle, Robert C Newton, Richard Schaub, Janet Maleski, Lance Leopold, Thomas F Gajewski
PURPOSE: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase 1 study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1. PATIENTS AND METHODS: Fifty-two patients with advanced solid malignancies were treated with epacadostat (50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily [BID]) in a dose-escalation 3 + 3 design and evaluated in 28-day cycles...
January 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28050790/first-in-human-study-of-the-antibody-dr5-agonist-ds-8273a-in-patients-with-advanced-solid-tumors
#19
Andres Forero, Johanna C Bendell, Prasanna Kumar, Linda Janisch, Michael Rosen, Qiang Wang, Catherine Copigneaux, Madhuri Desai, Giorgio Senaldi, Michael L Maitland
Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors. Methods The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks)...
January 3, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28050651/primary-transoral-robotic-surgery-with-concurrent-neck-dissection-for-early-stage-oropharyngeal-squamous-cell-carcinoma-implemented-at-a-danish-head-and-neck-cancer-center-a-phase-ii-trial-on-feasibility-and-tumour-margin-status
#20
Niclas Rubek, Hani Ibrahim Channir, Birgitte Wittenborg Charabi, Christel Bræmer Lajer, Katalin Kiss, Hans Ulrik Nielsen, Jens Bentzen, Jeppe Friborg, Christian von Buchwald
There is an increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the western world due to human papillomavirus (HPV). According to the Danish Head and Neck Cancer Group guidelines, the current recommended treatment of patients with OPSCC in Denmark is primary radiation therapy (RT) with or without concomitant chemotherapy. This is the first study in Scandinavia from a head and neck cancer centre that aims to demonstrate the feasibility of performing primary transoral robotic surgery (TORS) and concurrent neck dissection for patients with early stage OPSCC...
January 3, 2017: European Archives of Oto-rhino-laryngology
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