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https://www.readbyqxmd.com/read/28932756/non-clinical-safety-and-efficacy-of-an-aav2-8-vector-administered-intravenously-for-treatment-of-mucopolysaccharidosis-type-vi
#1
Rita Ferla, Marialuisa Alliegro, Jean-Brice Marteau, Margherita Dell'Anno, Edoardo Nusco, Severine Pouillot, Stefania Galimberti, Maria Grazia Valsecchi, Vincent Zuliani, Alberto Auricchio
In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.TBG.hARSB produced under good manufacturing practice-like conditions...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28926521/blockade-of-hla-antibody-triggered-classical-complement-activation-in-sera-from-subjects-dosed-with-the-anti-c1s-monoclonal-antibody-tnt009-results-from-a-randomized-first-in-human-phase-1-trial
#2
Jakob Mühlbacher, Bernd Jilma, Markus Wahrmann, Johann Bartko, Farsad Eskandary, Christian Schörgenhofer, Michael Schwameis, Graham C Parry, James C Gilbert, Sandip Panicker, Georg A Böhmig
BACKGROUND: Complement may play a key role in antibody-mediated rejection. A promising therapeutic approach may be classical pathway (CP) inhibition at the level of early component C1. METHODS: In this first-in-human, double-blind, randomized placebo-controlled phase 1 trial, we evaluated the safety and complement inhibitory effect of TNT009, a humanized monoclonal anti-C1s antibody. Sixty-four adult healthy volunteers received either single (n = 48; 7 consecutive cohorts, 0...
October 2017: Transplantation
https://www.readbyqxmd.com/read/28926357/first-in-human-treatment-with-a-dendritic-cell-targeting-lentiviral-vector-expressing-ny-eso-1-lv305-induces-deep-durable-response-in-refractory-metastatic-synovial-sarcoma-patient
#3
Seth M Pollack, Hailing Lu, Sacha Gnjatic, Neeta Somaiah, Ryan B O'Malley, Robin L Jones, Frank J Hsu, Jan Ter Meulen
Effective induction of antitumor T cells is a pivotal goal of cancer immunotherapy. To this end, lentiviral vectors (LV) are uniquely poised to directly prime CD8 T-cell responses via transduction of dendritic cells in vivo and have shown promise as active cancer therapeutics in preclinical tumor models. However, until now, significant barriers related to production and regulation have prevented their widespread use in the clinic. We developed LV305, a dendritic cell-targeting, integration-deficient, replication incompetent LV from the ZVex platform, encoding the full-length cancer-testis antigen NY-ESO-1...
September 18, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28921650/antibody-drug-conjugates-as-cancer-therapeutics-past-present-and-future
#4
Heather E Vezina, Monette Cotreau, Tae H Han, Manish Gupta
Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28919776/safety-pharmacokinetics-and-pharmacodynamics-of-oral-omaveloxolone-rta-408-a-synthetic-triterpenoid-in-a-first-in-human-trial-of-patients-with-advanced-solid-tumors
#5
Ben C Creelan, Dmitry I Gabrilovich, Jhanelle E Gray, Charles C Williams, Tawee Tanvetyanon, Eric B Haura, Jeffrey S Weber, Geoffrey T Gibney, Joseph Markowitz, Joel W Proksch, Scott A Reisman, Mark D McKee, Melanie P Chin, Colin J Meyer, Scott J Antonia
BACKGROUND: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. METHODS: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28916246/pre-clinical-toxicology-considerations-for-vaccine-development
#6
REVIEW
Nabil Al-Humadi
Vaccine development requires pre-clinical toxicology studies, following good laboratory practice (GLP), before first in human (phase I) use. Many factors are critical in the final outcome of any pre-clinical toxicology study. The study design is one of these critical factors and should be carefully planned to avoid any false negative and/or false positive results. Preparation is another most critical factor in a successful study. Major changes in any procedure during the course of study should be avoided by all means...
September 12, 2017: Vaccine
https://www.readbyqxmd.com/read/28912376/a-recombinant-human-adamts-13-first-in-human-study-evaluating-pharmacokinetics-safety-and-tolerability-in-cttp-patients
#7
Marie Scully, Paul Knöbl, Karim Kentouche, Lawrence Rice, Jerzy Windyga, Reinhard Schneppenheim, Johanna A Kremer Hovinga, Michiko Kajiwara, Yoshihiro Fujimura, Caterina Maggiore, Jennifer Doralt, Christopher Hibbard, Leah Martell, Bruce Ewenstein
Safety, tolerability and pharmacokinetics of recombinant ADAMTS-13 (rADAMTS-13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity < 6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. Following single dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to Cmax and AUC...
September 14, 2017: Blood
https://www.readbyqxmd.com/read/28893587/current-nonclinical-testing-paradigm-enables-safe-entry-to-first-in-human-clinical-trials-the-iq-consortium-nonclinical-to-clinical-translational-database
#8
Thomas M Monticello, Thomas W Jones, Donna M Dambach, David M Potter, Michael W Bolt, Maggie Liu, Douglas A Keller, Timothy K Hart, Vivek J Kadambi
The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis...
September 8, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28891906/first-in-human-treatment-with-a-dendritic-cell-targeting-lentiviral-vector-expressing-ny-eso-1-lv305-induces-deep-durable-response-in-refractory-metastatic-synovial-sarcoma-patient
#9
Seth M Pollack, Hailing Lu, Sacha Gnjatic, Neeta Somaiah, Ryan B O'Malley, Robin L Jones, Frank J Hsu, Jan Ter Meulen
Effective induction of antitumor T cells is a pivotal goal of cancer immunotherapy. To this end, lentiviral vectors (LV) are uniquely poised to directly prime CD8 T-cell responses via transduction of dendritic cells in vivo and have shown promise as active cancer therapeutics in preclinical tumor models. However, until now, significant barriers related to production and regulation have prevented their widespread use in the clinic. We developed LV305, a dendritic cell-targeting, integration-deficient, replication incompetent LV from the ZVex platform, encoding the full-length cancer-testis antigen NY-ESO-1...
October 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28887049/an-fda-oncology-analysis-of-cd3-bispecific-constructs-and-first-in-human-dose-selection
#10
Haleh Saber, Pedro Del Valle, Tiffany K Ricks, John K Leighton
We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab...
September 5, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28886699/research-on-advanced-intervention-using-novel-bone-marrow-stem-cell-rainbow-a-study-protocol-for-a-phase-i-open-label-uncontrolled-dose-response-trial-of-autologous-bone-marrow-stromal-cell-transplantation-in-patients-with-acute-ischemic-stroke
#11
Hideo Shichinohe, Masahito Kawabori, Hiroaki Iijima, Tuyoshi Teramoto, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Shunsuke Terasaka, Teruyo Arato, Kiyohiro Houkin
BACKGROUND: Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke...
September 8, 2017: BMC Neurology
https://www.readbyqxmd.com/read/28881846/safety-and-efficacy-of-p62-dna-vaccine-elenagen-in-a-first-in-human-trial-in-patients-with-advanced-solid-tumors
#12
Dmitry M Ponomarenko, Irina D Klimova, Yulia A Chapygina, Viktoria V Dvornichenko, Natalia V Zhukova, Rashida V Orlova, Georgy M Manikhas, Alexandr V Zyryanov, Lilya A Burkhanova, Irina I Badrtdinova, Basile N Oshchepkov, Elena V Filippova, Sergei V Orlov, Sergei I Kolesnikov, Albert A Sufianov, Svetlana R Baum, Olga Y Zaitzeva, Andrey B Komissarov, Mikhail P Grudinin, Oleg I Kiselev, Anatoly F Tsyb, Franco Venanzi, Vita Shcherbinina, Andrey Chursov, Vladimir L Gabai, Alexander M Shneider
Elenagen is a plasmid encoding p62/SQSTM1, the first DNA vaccine possessing two mutually complementing mechanisms of action: it elicits immune response against p62 and mitigates systemic chronic inflammation. Previously, Elenagen demonstrated anti-tumor efficacy and safety in rodent tumor models and spontaneous tumors in dogs. This multicenter I/IIa trial evaluated safety and clinical activity of Elenagen in patients with advanced solid tumors. Fifteen patients were treated with escalating doses of Elenagen (1- 5 mg per doses, 5 times weekly) and additional 12 patients received 1 mg dose...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880867/oral-tetrahydrouridine-and-decitabine-for-non-cytotoxic-epigenetic-gene-regulation-in-sickle-cell-disease-a-randomized-phase-1-study
#13
RANDOMIZED CONTROLLED TRIAL
Robert Molokie, Donald Lavelle, Michel Gowhari, Michael Pacini, Lani Krauz, Johara Hassan, Vinzon Ibanez, Maria A Ruiz, Kwok Peng Ng, Philip Woost, Tomas Radivoyevitch, Daisy Pacelli, Sherry Fada, Matthew Rump, Matthew Hsieh, John F Tisdale, James Jacobberger, Mitch Phelps, James Douglas Engel, Santhosh Saraf, Lewis L Hsu, Victor Gordeuk, Joseph DeSimone, Yogen Saunthararajah
BACKGROUND: Sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) interferes with this polymerization, but HbF is epigenetically silenced from infancy onward by DNA methyltransferase 1 (DNMT1). METHODS AND FINDINGS: To pharmacologically re-induce HbF by DNMT1 inhibition, this first-in-human clinical trial (NCT01685515) combined 2 small molecules-decitabine to deplete DNMT1 and tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that otherwise rapidly deaminates/inactivates decitabine, severely limiting its half-life, tissue distribution, and oral bioavailability...
September 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28880460/cryopreserved-off-the-shelf-allogeneic-adipose-derived-stromal-cells-for-therapy-in-patients-with-ischemic-heart-disease-and-heart-failure-a-safety-study
#14
Jens Kastrup, Mandana Haack-Sørensen, Morten Juhl, Rebekka Harary Søndergaard, Bjarke Follin, Lisbeth Drozd Lund, Ellen Mønsted Johansen, Abbas Ali Qayyum, Anders Bruun Mathiasen, Erik Jørgensen, Steffen Helqvist, Jens Jørgen Elberg, Helle Bruunsgaard, Annette Ekblond
The present first-in-human clinical trial evaluated the safety and feasibility of a newly developed and cryopreserved Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors for intramyocardial injection in ten patients with ischemic heart disease and ischemic heart failure (IHF). Batches of CSCC_ASC were isolated from three healthy donors by liposuction from abdominal adipose tissue. Adipose mesenchymal stromal cells were culture expanded in bioreactors without the use of animal constituents, cryopreserved, and stored in vials in nitrogen dry-storage containers until use...
September 7, 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28870716/endovascular-baroreflex-amplification-for-resistant-hypertension-a-safety-and-proof-of-principle-clinical-study
#15
Wilko Spiering, Bryan Williams, Jan Van der Heyden, Monique van Kleef, Rob Lo, Jorie Versmissen, Adriaan Moelker, Abraham Kroon, Hannes Reuter, Gary Ansel, Gregg W Stone, Mark Bates
BACKGROUND: Carotid baroreflex activation lowers blood pressure and might have potential application for the treatment of resistant hypertension. We did a proof-of-principle trial with a novel endovascular baroreceptor amplification device, MobiusHD (Vascular Dynamics, Mountain View, CA, USA), in patients with resistant hypertension. METHODS: CALM-FIM_EUR was a prospective, first-in-human, open-label study done at six European centres. Eligible patients were adults with resistant hypertension (office systolic blood pressure ≥160 mm Hg despite taking at least three antihypertensive agents, including a diuretic)...
September 1, 2017: Lancet
https://www.readbyqxmd.com/read/28864607/glu-ureido-based-inhibitors-of-prostate-specific-membrane-antigen-lessons-learned-during-the-development-of-a-novel-class-of-low-molecular-weight-theranostic-radiotracers
#16
Klaus Kopka, Martina Benešová, Cyril Bařinka, Uwe Haberkorn, John Babich
In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21(st) century, a new era in nuclear medicine was initiated by the clinical introduction of small-molecule PSMA inhibitor radioligands, 40 y after the clinical introduction of (18)F-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clinical management of PC...
September 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28860210/safety-and-persistence-of-wt1-specific-t-cell-receptor-gene-transduced-lymphocytes-in-patients-with-aml-and-mds
#17
Isao Tawara, Shinichi Kageyama, Yoshihiro Miyahara, Hiroshi Fujiwara, Tetsuya Nishida, Yoshiki Akatsuka, Hiroaki Ikeda, Kazushi Tanimoto, Seitaro Terakura, Makoto Murata, Yoko Inaguma, Masahiro Masuya, Naoki Inoue, Tomohide Kidokoro, Sachiko Okamoto, Daisuke Tomura, Hideto Chono, Ikuei Nukaya, Junichi Mineno, Tomoki Naoe, Nobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku
WT1 is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in human trial of TCR-gene transduced T cell (TCR-T cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding siRNAs for endogenous TCR genes...
August 31, 2017: Blood
https://www.readbyqxmd.com/read/28854070/first-in-human-phase-i-study-of-the-tamoxifen-metabolite-z-endoxifen-in-women-with-endocrine-refractory-metastatic-breast-cancer
#18
Matthew P Goetz, Vera J Suman, Joel M Reid, Don W Northfelt, Michael A Mahr, Andrew T Ralya, Mary Kuffel, Sarah A Buhrow, Stephanie L Safgren, Renee M McGovern, John Black, Travis Dockter, Tufia Haddad, Charles Erlichman, Alex A Adjei, Dan Visscher, Zachary R Chalmers, Garrett Frampton, Benjamin R Kipp, Minetta C Liu, John R Hawse, James H Doroshow, Jerry M Collins, Howard Streicher, Matthew M Ames, James N Ingle
Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day...
August 30, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28846544/first-in-human-implantation-of-a-novel-transfemoral-self-expanding-transcatheter-heart-valve-to-treat-pure-aortic-regurgitation
#19
Ulrich Schäfer, Johannes Schirmer, Niklas Schofer, Eva Harmel, Florian Deuschl, Lenard Conradi
The first case of a novel JenaValve design using the transfemoral approach in a 78 year old female patient with pure aortic regurgitation is described. The implantation was successfully performed with excellent haemodynamics and good clinical outcome at 6 months follow up. The technology is especially appealing in non-calcified anatomies due to the clipping mechanism that has been previously utilized in the transapical design.
August 29, 2017: EuroIntervention
https://www.readbyqxmd.com/read/28843832/magnetic-compression-anastomosis-magnamosis-first-in-human-trial
#20
Claire E Graves, Catherine Co, Ryan S Hsi, Dillon Kwiat, Jill Imamura-Ching, Michael R Harrison, Marshall L Stoller
BACKGROUND: Magnetic compression anastomosis (magnamosis) uses a pair of self-centering magnetic Harrison Rings to create an intestinal anastomosis without sutures or staples. We report the first-in-human case series using this unique device. STUDY DESIGN: We conducted a prospective, single-center, first-in-human pilot trial to evaluate the feasibility and safety of creating an intestinal anastomosis using the Magnamosis device. Adult patients requiring any intestinal anastomosis to restore bowel continuity were eligible for inclusion...
August 23, 2017: Journal of the American College of Surgeons
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