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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
#1
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/28077588/first-in-human-evaluation-of-the-safety-and-immunogenicity-of-an-intranasally-administered-replication-competent-sendai-virus-vectored-hiv-type-1-gag-vaccine-induction-of-potent-t-cell-or-antibody-responses-in-prime-boost-regimens
#2
Julien Nyombayire, Omu Anzala, Brian Gazzard, Etienne Karita, Philip Bergin, Peter Hayes, Jakub Kopycinski, Gloria Omosa-Manyonyi, Akil Jackson, Jean Bizimana, Bashir Farah, Eddy Sayeed, Christopher L Parks, Makoto Inoue, Takashi Hironaka, Hiroto Hara, Tsugumine Shu, Tetsuro Matano, Len Dally, Burc Barin, Harriet Park, Jill Gilmour, Angela Lombardo, Jean-Louis Excler, Patricia Fast, Dagna S Laufer, Josephine H Cox
BACKGROUND:  We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. METHODS:  Sixty-five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35-vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH)...
January 1, 2017: Journal of Infectious Diseases
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
#3
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/28070718/first-in-human-trial-of-an-anti-5t4-antibody-monomethylauristatin-conjugate-pf-06263507-in-patients-with-advanced-solid-tumors
#4
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/28069570/anti-cd22-car-therapy-leads-to-all-remissions
#5
(no author information available yet)
In a first-in-human trial of an anti-CD22 chimeric antigen receptor T-cell therapy in children and young adults with relapsed and refractory acute lymphocytic leukemia, researchers found that the immunotherapeutic approach was not only feasible and safe, but also effective, leading to remissions in most patients. Infusions of higher numbers of T cells correlated with improved responses.
January 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28064353/who-is-a-healthy-subject-consensus-results-on-pivotal-eligibility-criteria-for-clinical-trials
#6
REVIEW
Kerstin Breithaupt-Groegler, Christoph Coch, Martin Coenen, Frank Donath, Katharina Erb-Zohar, Klaus Francke, Karin Goehler, Mario Iovino, Klaus Peter Kammerer, Gerd Mikus, Jens Rengelshausen, Hildegard Sourgens, Reinhard Schinzel, Thomas Sudhop, Georg Wensing
INTRODUCTION/METHODS: A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority. RESULTS: Pivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs...
January 7, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28057550/pharmacokinetics-of-lbpt-and-its-primary-metabolites-as-well-as-tolerability-in-the-first-in-human-study
#7
Hongyun Wang, Hongzhong Liu, Ming Liu, Wenjie Wang, Liya Zhu, Haihong Huang, Pei Hu, Ji Jiang
BACKGROUND: LBPT is a novel platelet-activating factor (PAF) receptor antagonist that is developed for the treatment of rheumatoid arthritis. The purpose of this first-in-human study was to evaluate the tolerability and safety of LBPT, to investigate the pharmacokinetics of LBPT and its primary metabolites, as well as to assess the food effect on the pharmacokinetics in healthy Chinese subjects. MATERIALS AND METHODS: LBPT was evaluated in 2 clinical studies. The first study was a double blind, placebo-controlled and ascending dose study...
January 2, 2017: European Journal of Pharmaceutical Sciences
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
#8
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
#9
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/28052545/safety-feasibility-and-effectiveness-of-first-in-human-administration-of-muscle-derived-stem-progenitor-cells-modified-with-connexin-43-gene-for-treatment-of-advanced-chronic-heart-failure
#10
Adrian Gwizdala, Natalia Rozwadowska, Tomasz Jan Kolanowski, Agnieszka Malcher, Aleksandra Cieplucha, Bartlomiej Perek, Wojciech Seniuk, Ewa Straburzynska-Migaj, Zofia Oko-Sarnowska, Witold Cholewinski, Michal Michalak, Stefan Grajek, Maciej Kurpisz
AIMS: To assess the safety and efficacy of transendocardial delivery of muscle-derived stem/progenitor cells with connexin-43 overexpression (Cx-43-MDS/PC) in advanced heart failure (HF). METHODS AND RESULTS: Thirteen subjects with advanced HF, New York Heart Association (NYHA) class II-III were enrolled and treated with targeted injection of Cx-43-MDS/PCs and then monitored for at least 6 months. Overexpression of Cx43 (Cx43+) was significantly higher in all but one subject (Cx43-)...
January 2017: European Journal of Heart Failure
https://www.readbyqxmd.com/read/28050790/first-in-human-study-of-the-antibody-dr5-agonist-ds-8273a-in-patients-with-advanced-solid-tumors
#11
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/28050141/stakeholder-views-on-participant-selection-for-first-in-human-trials-in-cancer-nanomedicine
#12
P Satalkar, B S Elger, D M Shaw
BACKGROUND: Participant selection for first-in-human (fih) trials involves complex decisions. The trial design makes it unlikely that participants will receive clinically relevant therapeutic benefit, but they are likely to experience risks of various magnitudes and types. The aim of the present paper was to describe and discuss the views of investigators and ethics committee members about the choice of trial participants for fih trials in cancer nanomedicine. METHODS: We drew insights from an exploratory qualitative study involving thematic analysis of 46 in-depth interviews with key stakeholders in Europe and North America involved in fih nanomedicine trials...
December 2016: Current Oncology
https://www.readbyqxmd.com/read/28049891/development-of-cellular-and-tissue-based-products-for-retinal-regenerative-medicine
#13
Fumitaka Osakada
 Since the discovery of induced pluripotent stem cells (iPSCs) generation, much progress has been made in the fields of medical and pharmaceutical research, such as cell transplantation therapy. We have generated retinal cells and tissues, including retinal pigment epithelia (RPE), from human iPSCs. The ability to produce iPSCs from patients allows for autologous transplantation without causing immune rejection. The autologous transplantation of iPSC-derived retinal pigment epithelial sheets to a patient with age-related macular degeneration was carried out in Japan in 2014 as a first-in-human clinical study...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28047009/su-f-j-181-an-alternative-patient-alignment-tool-on-tomotherapy-the-first-in-human-megavoltage-topogram-acquisition
#14
L Yang, D Low, P Lee, D Ruan, R Chin, T Kaprealian, M Kamrava, P Kupelian, P Beron, M Steinberg, A Chen, N Agazaryan, S Ray, X Qi
PURPOSE: To show the first in-human Megavoltage (MV)-Topogram acquisition for the evaluation of the potential for MV-Topogram-based alignment as an alternative to MVCT for reducing dose and imaging time. METHODS: A lung cancer patient was enrolled in an ongoing IRB-approved clinical trial at our institute. The patient was set up using the clinical protocol employing positioning lasers. 3.2mm diameter tungsten spheres were placed on the patient's skin at their alignment tattoos to check surface-based marker concordance between topograms and MVCT...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28028691/sirolimus-therapy-is-associated-with-elevation-in-circulating-pcsk9-levels-in-cardiac-transplant-patients
#15
Vinaya Simha, Sisi Qin, Pankaj Shah, Byron H Smith, Walter K Kremers, Sudhir Kushwaha, Liewei Wang, Naveen L Pereira
Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 ± 105 ng/mL to 343 ± 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0...
December 27, 2016: Journal of Cardiovascular Translational Research
https://www.readbyqxmd.com/read/28027810/first-in-human-safety-and-immunogenicity-investigations-of-three-adjuvanted-reduced-dose-inactivated-poliovirus-vaccines-ipv-al-ssi-compared-to-full-dose-ipv-vaccine-ssi-when-given-as-a-booster-vaccination-to-adolescents-with-a-history-of-ipv-vaccination-at
#16
Line M Lindgren, Pernille N Tingskov, Annette H Justesen, Bettina S Nedergaard, Klaus J Olsen, Lars V Andreasen, Ingrid Kromann, Charlotte Sørensen, Jes Dietrich, Birgit Thierry-Carstensen
BACKGROUND: There is a demand of affordable IPV in the World. Statens Serum Institut (SSI) has developed three reduced dose IPV formulations adsorbed to aluminium hydroxide; 1/3 IPV-Al, 1/5 IPV-Al and 1/10 IPV-Al SSI, and now report the results of the first investigations in humans. METHODS: 240 Danish adolescents, aged 10-15years, and childhood vaccinated with IPV were booster vaccinated with 1/3 IPV-Al, 1/5 IPV-Al, 1/10 IPV-Al or IPV Vaccine SSI. The booster effects (GMTRs) of the three IPV-Al SSI were compared to IPV Vaccine SSI, and evaluated for non-inferiority...
December 24, 2016: Vaccine
https://www.readbyqxmd.com/read/28002882/pharmacokinetics-and-safety-of-a-single-dose-of-the-novel-necrosis-inhibitor-lc28-0126-in-healthy-male-subjects
#17
Seokuee Kim, Hyewon Chung, Seung Hwan Lee, Sang-Heon Cho, Hyun-Jai Cho, Soon Ha Kim, In-Jin Jang, Kyung-Sang Yu
AIMS: A novel necrosis inhibitor, LC28-0126, is expected to have a cellular protective effect from ischaemic reperfusion injury in acute myocardial infarction. The objective of this study was to investigate the safety, tolerability and pharmacokinetics of LC28-0126 after a single intravenous administration in healthy male subjects. METHODS: The study was a dose-block-randomized, double-blind, placebo-controlled, single ascending dose, first-in-human trial. Subjects were randomly assigned to receive 0...
December 21, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27998887/first-in-human-study-testing-a-new-radioenhancer-using-nanoparticles-nbtxr3-activated-by-radiation-therapy-in-patients-with-locally-advanced-soft-tissue-sarcomas
#18
Sylvie Bonvalot, Cécile Le Pechoux, Thierry De Baere, Guy Kantor, Xavier Buy, Eberhard Stoeckle, Philippe Terrier, Paul Sargos, Jean Michel Coindre, Nathalie Lassau, Rafik Ait Sarkouh, Mikaela Dimitriu, Elsa Borghi, Laurent Levy, Eric Deutsch, Jean-Charles Soria
PURPOSE: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS). EXPERIMENTAL DESIGN: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI...
October 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27995439/immuno-oncology-the-third-paradigm-in-early-drug-development
#19
Juan Martin-Liberal, Cinta Hierro, Maria Ochoa de Olza, Jordi Rodon
Clinical researchers in oncology face the difficulty of developing new drugs for treating cancer patients. This challenge nowadays extends towards new horizons since a high number of drugs are developed in each of the three paradigms: classical cytotoxics, new targeted agents, and emergent immunotherapeutic approaches. Over the last decade, there has been an unstoppable progress in this third paradigm, to the extent that in 2013 immunotherapy was granted the scientific breakthrough of the year. However, the novel mechanisms of action of these immunotherapeutic agents entail a whole new series of concepts, resulting in a number of unresolved questions to which clarification is crucial for their success: establishment of accurate preclinical models able to predict human toxicities, better selection of candidate populations, finding and validation of predictive biomarkers, definition of suitable endpoints, improvements in first-in-human study designs, proposal of more accurate radiological response criteria, management of novel immune-related toxicities and development of combinations based on a biological rationale...
December 20, 2016: Targeted Oncology
https://www.readbyqxmd.com/read/27994442/determination-of-the-starting-dose-in-the-first-in-human-clinical-trials-with-monoclonal-antibodies-a-systematic-review-of-papers-published-between-1990-and-2013
#20
Hoon Young Suh, Carl C Peck, Kyung-Sang Yu, Howard Lee
A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps...
2016: Drug Design, Development and Therapy
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