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https://www.readbyqxmd.com/read/27923840/osimertinib-for-the-treatment-of-metastatic-epidermal-growth-factor-t970m-positive-non-small-cell-lung-cancer
#1
Sean Khozin, Chana Weinstock, Gideon M Blumenthal, Joyce Cheng, Kun He, Luning Zhuang, Hong Zhao, Rosane Charlab Orbach, Ingrid Fan, Patricia Keegan, Richard Pazdur
On November 13, 2015, FDA granted accelerated approval to osimertinib (TAGRISSO™; AstraZeneca), a breakthrough therapy-designated drug for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, with progression on or after EGFR tyrosine kinase inhibitor therapy. Approval was based on durable tumor response rates in two single-arm, multicenter trials: the dose extension cohort of a first-in-human trial (AURA extension; n=201) and a fixed-dose, activity-estimating trial (AURA2; n=210)...
December 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27920527/pharmacokinetics-and-safety-of-dts-108-a-human-oligopeptide-bound-to-sn-38-with-an-esterase-sensitive-cross-linker-in-patients-with-advanced-malignancies-a-phase-i-study
#2
Romain Coriat, Sandrine J Faivre, Olivier Mir, Chantal Dreyer, Stanislas Ropert, Mohammed Bouattour, Robert Desjardins, François Goldwasser, Eric Raymond
BACKGROUND: DTS-108 is a hydrosoluble prodrug, where the SN-38 moiety is covalently linked to a 20-amino acid vector peptide by a specific esterase-sensitive cross-linker, releasing 7-ethyl-10-hydroxycampthotecin (SN-38) by esterase bond cleavage. METHODS: The pharmacokinetics of DTS-108, adverse events graded according to NCI-CTCv3.1, dose-limiting toxicities at cycle 1, the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of intravenous DTS-108 (1-2 hours) every 2 weeks were evaluated in a first-in-human Phase I study in patients with advanced/metastatic carcinomas, according to an accelerated dose escalation design...
2016: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/27917453/phase-i-study-of-mrx34-a-liposomal-mir-34a-mimic-administered-twice-weekly-in-patients-with-advanced-solid-tumors
#3
Muhammad S Beg, Andrew J Brenner, Jasgit Sachdev, Mitesh Borad, Yoon-Koo Kang, Jay Stoudemire, Susan Smith, Andreas G Bader, Sinil Kim, David S Hong
Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial...
December 5, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27916408/safety-tolerability-and-immunogenicity-of-a-4-antigen-staphylococcus-aureus-vaccine-sa4ag-results-from-a-first-in-human-randomised-placebo-controlled-phase-1-2-study
#4
Robert W Frenck, C Buddy Creech, Eric A Sheldon, David J Seiden, Martin K Kankam, James Baber, Edward Zito, Robin Hubler, Joseph Eiden, Joseph M Severs, Shite Sebastian, Jasdeep Nanra, Kathrin U Jansen, William C Gruber, Annaliesa S Anderson, Douglas Girgenti
BACKGROUND: A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. METHODS: In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18-64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo...
December 1, 2016: Vaccine
https://www.readbyqxmd.com/read/27906723/safety-and-outcome-measures-of-first-in-human-intraperitoneal-%C3%AE-radioimmunotherapy-with-212pb-tcmc-trastuzumab
#5
Ruby F Meredith, Julien J Torgue, Tania A Rozgaja, Eileen P Banaga, Patty W Bunch, Ronald D Alvarez, J Michael Straughn, Michael C Dobelbower, Andrew M Lowy
PURPOSE: One-year monitoring of patients receiving intraperitoneal (IP) Pb-TCMC-trastuzumab to provide long-term safety and outcome data. A secondary objective was to study 7 tumor markers for correlation with outcome. METHODS: Eighteen patients with relapsed intra-abdominal human epidermal growth factor receptor-2 expressing peritoneal metastases were treated with a single IP infusion of Pb-TCMC-trastuzumab, delivered <4 h after 4 mg/kg IV trastuzumab. Seven tumor markers were studied for correlation with outcome...
November 30, 2016: American Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27900338/the-bridge-enhanced-anterior-cruciate-ligament-repair-bear-procedure-an-early-feasibility-cohort-study
#6
Martha M Murray, Brett M Flutie, Leslie A Kalish, Kirsten Ecklund, Braden C Fleming, Benedikt L Proffen, Lyle J Micheli
BACKGROUND: This study assessed the safety of the newly developed bridge-enhanced anterior cruciate ligament (ACL) repair (BEAR), which involves suture repair of the ligament combined with a bioactive scaffold to bridge the gap between the torn ligament ends. As the intra-articular environment is complex in its response to implanted materials, this study was designed to determine whether there would be a significant rate of adverse reaction to the implanted scaffold. HYPOTHESIS: The primary hypothesis was that the implanted scaffold would not result in a deep joint infection (arthrocentesis with positive culture) or significant inflammation (clinical symptoms justifying arthrocentesis but negative culture)...
November 2016: Orthopaedic Journal of Sports Medicine
https://www.readbyqxmd.com/read/27894931/the-unique-status-of-first-in-human-studies-strengthening-the-social-value-requirement
#7
Michelle G J L Habets, Johannes J M van Delden, Annelien L Bredenoord
For clinical research to be ethical, risks need to be balanced by anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly, and risks are potentially high. We argue that this differentiates FIH studies from other clinical trials to the extent that they should be given unique status in international research ethics guidelines. As there is a general positive attitude regarding the benefits of science, it is important to establish a more systematic method to assess anticipated social value to safeguard participants not only from enrolling in risky, but also in futile trials...
November 25, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27887864/optimization-of-cgmp-purification-and-expansion-of-umbilical-cord-blood-derived-t-regulatory-cells-in-support-of-first-in-human-clinical-trials
#8
David H McKenna, Darin Sumstad, Diane M Kadidlo, Bjorn Batdorf, Colin J Lord, Sarah C Merkel, Christine M Koellner, Julie M Curtsinger, Carl H June, James L Riley, Bruce L Levine, Jeffrey S Miller, Claudio G Brunstein, John E Wagner, Bruce R Blazar, Keli L Hippen
BACKGROUND AIMS: Thymic-derived regulatory T cells (tTreg) are critical regulators of the immune system. Adoptive tTreg transfer is a curative therapy for murine models of autoimmunity, graft rejection, and graft-versus-host disease (GVHD). We previously completed a "first-in-human" clinical trial using in vitro expanded umbilical cord blood (UCB)-derived tTreg to prevent GVHD in patients undergoing UCB hematopoietic stem cell transplantation (HSCT). tTreg were safe and demonstrated clinical efficacy, but low yield prevented further dose escalation...
November 22, 2016: Cytotherapy
https://www.readbyqxmd.com/read/27886407/first-in-human-assessment-of-prx002-an-anti-%C3%AE-synuclein-monoclonal-antibody-in-healthy-volunteers
#9
Dale B Schenk, Martin Koller, Daniel K Ness, Sue G Griffith, Michael Grundman, Wagner Zago, Jay Soto, George Atiee, Susanne Ostrowitzki, Gene G Kinney
BACKGROUND: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0...
November 25, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27878643/the-evolution-of-drug-design-at-merck-research-laboratories
#10
Frank K Brown, Edward C Sherer, Scott A Johnson, M Katharine Holloway, Bradley S Sherborne
On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc...
November 23, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27872317/first-in-human-experience-with-the-gore-balloon-expandable-covered-endoprosthesis-in-iliac-artery-occlusive-disease
#11
Andrew Holden, Stephen Merrilees, Brendan Buckley, Brigid Connor, Frances Colgan, Andrew Hill
PURPOSE: To report the first-in-human iliac artery experience of a new balloon-expandable covered endoprosthesis. METHODS: A prospective, single-center pilot study recruited 30 symptomatic patients (mean age 64 years; 18 men) to evaluate the safety and early efficacy of the new Gore balloon-expandable covered endoprosthesis for the treatment of de novo or restenotic common and/or external iliac artery lesions. According to protocol, up to 2 discrete lesions could be treated with a maximum total treated length ≤110 mm...
November 21, 2016: Journal of Endovascular Therapy
https://www.readbyqxmd.com/read/27872130/a-first-in-human-phase-i-study-of-the-atp-competitive-akt-inhibitor-ipatasertib-gdc-0068-demonstrates-robust-and-safe-targeting-of-akt-in-patients-with-solid-tumors
#12
Cristina Saura, Desamparados Roda, Susana Roselló, Mafalda Oliveira, Teresa Macarulla, José Alejandro Pérez-Fidalgo, Rafael Morales-Barrera, Juan Manuel Sanchis-García, Luna Musib, Nageshwar Budha, Jin Zhu, Michelle Nannini, Wai Y Chan, Sandra M Sanabria Bohórquez, Raymond D Meng, Kui Lin, Yibing Yan, Premal Patel, José Baselga, Josep Tabernero, Andres Cervantes
Activation of Akt signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers but targeting Akt has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of Akt. Ipatasertib (GDC‑0068) is a novel selective ATP-competitive small molecule inhibitor of Akt that preferentially targets active phosphorylated Akt and is potent in cell lines with evidence of Akt activation. In this Phase I study, ipatasertib was well-tolerated; most adverse events were gastrointestinal and Grade 1-2 in severity...
November 21, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27870924/evaluating-mesenchymal-stem-cell-therapy-for-sepsis-with-preclinical-meta-analyses-prior-to-initiating-a-first-in-human-trial
#13
Manoj M Lalu, Katrina J Sullivan, Shirley Hj Mei, David Moher, Alexander Straus, Dean A Fergusson, Duncan J Stewart, Mazen Jazi, Malcolm MacLeod, Brent Winston, John Marshall, Brian Hutton, Keith R Walley, Lauralyn McIntyre
Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality (odds ratio 0...
November 17, 2016: ELife
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
#14
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...
November 21, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27866008/organs-on-chips-research-and-commercial-perspectives
#15
REVIEW
Aarathi Balijepalli, Vaibhav Sivaramakrishan
Traditional preclinical drug testing methods utilize animal models to predict pharmacology and toxicology profiles. However, the data obtained from such methods cannot be directly extrapolated to humans and often do not provide a safe starting dose for first-in-human studies. To overcome these limitations, researchers have developed organs-on-chips - microfluidic devices that can mimic the cellular architecture and physiology more accurately than conventional methods. Because accurate organ-level interactions can be achieved with these devices, they have the potential to provide a realistic determination of a drug's pharmacokinetics, pharmacodynamics and toxicity profile...
November 16, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27863806/pharmacokinetics-safety-and-tolerability-of-single-and-multiple-doses-of-abt-493-a-first-in-human-study
#16
Chih-Wei Lin, Sandeep Dutta, Armen Asatryan, Yi-Lin Chiu, Haoyu Wang, Jack Clifton, Andrew Campbell, Wei Liu
ABT-493 is a hepatitis C virus nonstructural protein 3/4A protease inhibitor with pangenotypic antiviral activity. This study investigated the pharmacokinetics, safety, and tolerability of single and multiple ascending doses of ABT-493 and the effect of food and ritonavir coadministration on ABT-493 pharmacokinetics in healthy adults. In the blinded, randomized, placebo-controlled phase 1 single- and multiple-dose portions of the study, ABT-493 25-800 mg were evaluated as single doses, and 200, 400, and 800 mg were evaluated as multiple doses...
November 15, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27859546/first-in-human-randomised-study-of-bimekizumab-a-humanised-monoclonal-antibody-and-selective-dual-inhibitor-of-il-17a-and-il-17%C3%A2-f-in-mild-psoriasis
#17
S Glatt, E Helmer, B Haier, F Strimenopoulou, G Price, P Vajjah, O A Harari, J Lambert, S Shaw
AIMS: Assess safety, pharmacokinetics (PK) and clinical efficacy of bimekizumab, (formerly UCB4940), a novel humanised monoclonal antibody and dual inhibitor of interleukin (IL)-17A and IL-17 F, in subjects with mild plaque psoriasis. METHODS: Randomised, double-blind, first-in-human study of bimekizumab in 39 subjects who received single-dose intravenous (iv) bimekizumab (8-640 mg) or placebo (NCT02529956). RESULTS: Bimekizumab demonstrated dose-proportional linear PK and was tolerated across the dose range assessed...
November 13, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27852477/transcatheter-mitral-valve-replacement
#18
REVIEW
Ala Al-Lawati, Anson Cheung
Mitral valve disease prevalence is on the rise worldwide, affecting an estimated 2% of the general population. Novel transcatheter mitral valve replacement technologies are being developed and may provide a viable and safe option in patients who are deemed otherwise not suitable candidates for conventional mitral valve surgery. This article reviews these devices and describes trials of first in-human use.
January 2016: Interventional cardiology clinics
https://www.readbyqxmd.com/read/27849166/first-in-human-study-in-healthy-subjects-with-fr104-a-pegylated-monoclonal-antibody-fragment-antagonist-of-cd28
#19
Nicolas Poirier, Gilles Blancho, Maryvonne Hiance, Caroline Mary, Tim Van Assche, Jos Lempoels, Steven Ramael, Weirong Wang, Virginie Thepenier, Cecile Braudeau, Nina Salabert, Regis Josien, Ian Anderson, Ian Gourley, Jean-Paul Soulillou, Didier Coquoz, Bernard Vanhove
FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27844212/a-first-in-human-randomized-controlled-subject-and-reviewer-blinded-multicenter-study-of-actamax%C3%A2-adhesion-barrier
#20
Geoffrey H Trew, George A Pistofidis, Sara Y Brucker, Bernhard Krämer, Nicole M Ziegler, Matthias Korell, Henning Ritter, Alex McConnachie, Ian Ford, Alison M Crowe, Trudy D Estridge, Michael P Diamond, Rudy L De Wilde
PURPOSE: Post-surgical adhesions remain a significant concern following abdominopelvic surgery. This study was to assess safety, manageability and explore preliminary efficacy of applying a degradable hydrogel adhesion barrier to areas of surgical trauma following gynecologic laparoscopic abdominopelvic surgery. METHODS: This first-in-human, prospective, randomized, multicenter, subject- and reviewer-blinded clinical study was conducted in 78 premenopausal women (18-46 years) wishing to maintain fertility and undergoing gynecologic laparoscopic abdominopelvic surgery with planned clinically indicated second-look laparoscopy (SLL) at 4-12 weeks...
November 14, 2016: Archives of Gynecology and Obstetrics
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