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Phase I trials

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https://www.readbyqxmd.com/read/28921395/analysis-of-integrated-clinical-trial-protocols-in-early-phases-of-medicinal-product-development
#1
Kevin Fruhner, Gunther Hartmann, Thomas Sudhop
PURPOSE: While in the past, most clinical trial applications (CTAs) following non-integrated (standard) protocols were used to investigate one primary objective concerning a (new) drug, nowadays, the use of integrated protocols investigating multiple objectives within the same CTA becomes more and more popular. The aims of the present study were to investigate the usage and the impact of integrated protocols on regulatory activities and to find the motivation for their increasing use...
September 18, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28920616/vitamin-c-protects-piglet-liver-against-zearalenone-induced-oxidative-stress-by-modulating-expression-of-nuclear-receptors-pxr-and-car-and-their-target-genes
#2
Baoming Shi, Yang Su, Siying Chang, Yuchen Sun, Xiangyu Meng, Anshan Shan
Zearalenone (ZEN), one of the most common mycotoxins found in human food and animal feed, has been shown to be effectively detoxified by vitamin C (Vc). The aim of this study was to investigate how vitamin C protects the piglet liver against oxidative stress induced by ZEN. A total of thirty-two healthy female crossbred weaning piglets (Duroc × Landrace × Large white) with an initial weight of 12.27 ± 0.30 kg were randomly divided into four treatment groups of eight piglets per group. The dietary treatments included two zearalenone levels (0 mg kg(-1) and 1...
September 18, 2017: Food & Function
https://www.readbyqxmd.com/read/28920533/refinement-of-the-montreal-instrument-for-cat-arthritis-testing-for-use-by-veterinarians-detection-of-naturally-occurring-osteoarthritis-in-laboratory-cats
#3
Mary P Klinck, Beatriz P Monteiro, Bertrand Lussier, Martin Guillot, Maxim Moreau, Colombe Otis, Paulo Vm Steagall, Diane Frank, Johanne Martel-Pelletier, Jean-Pierre Pelletier, Jérôme Re Del Castillo, Eric Troncy
Objectives Feline osteoarthritis causes pain and disability. Detection and measurement is challenging, relying heavily on owner report. This study describes refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians. Methods A video analysis of osteoarthritic (n = 6) and non-osteoarthritic (n = 4) cats facilitated expansion of scale items. Three successive therapeutic trials (using gabapentin, tramadol and oral transmucosal meloxicam spray) in laboratory cats with and without natural osteoarthritis (n = 12-20), permitted construct validation (assessments of disease status sensitivity and therapeutic responsiveness) and further scale refinements based on performance...
September 1, 2017: Journal of Feline Medicine and Surgery
https://www.readbyqxmd.com/read/28920153/optimizing-somatostatin-analog-use-in-well-or-moderately-differentiated-gastroenteropancreatic-neuroendocrine-tumors
#4
REVIEW
Alberto Carmona-Bayonas, Paula Jiménez-Fonseca, Ana Custodio, Enrique Grande, Jaume Capdevila, Carlos López, Alex Teule, Rocío Garcia-Carbonero
BACKGROUND: Somatostatin analogues, aiming to control tumor secretion or growth, constitute the most attractive therapeutic option for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The objective of this article is to provide a comprehensive review of the current state-of-the-art knowledge gaps and potential opportunities for future development and optimization of this therapeutic modality. METHOD: A contextualized systematic review with a narrative component was conducted using PubMed, The Cochrane Library, EMBASE, and Google Scholar...
September 18, 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28920006/dosing-immunotherapy-combinations-analysis-of-3-526-patients-for-toxicity-and-response-patterns
#5
Mina Nikanjam, Harsh Patel, Razelle Kurzrock
Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage...
2017: Oncoimmunology
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
#6
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/28919772/anti-pcsk9-antibodies-for-the-treatment-of-heterozygous-familial-hypercholesterolemia-patient-selection-and-perspectives
#7
REVIEW
Alberico Luigi Catapano, Angela Pirillo, Giuseppe Danilo Norata
Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels from birth, which exposes the arteries to high levels of atherogenic lipoproteins lifelong and results in a significantly increased risk of premature cardiovascular events. The diagnosis of FH, followed by an appropriate and early treatment is critical to reduce the cardiovascular burden in this population. Phase I-III clinical trials showed the benefit of proprotein convertase subtilisin kexin 9 inhibitors, both alirocumab and evolocumab, in these patients with an average low-density lipoprotein cholesterol reduction ranging from -40% to -60%...
2017: Vascular Health and Risk Management
https://www.readbyqxmd.com/read/28919454/a-robust-immune-system-conditions-the-response-to-abagovomab-anti-idiotypic-monoclonal-antibody-mimicking-the-ca125-protein-vaccination-in-ovarian-cancer-patients
#8
Alessandra Battaglia, Marco Fossati, Alexia Buzzonetti, Giovanni Scambia, Andrea Fattorossi
INTRODUCTION: Despite encouraging phase I and II study results, vaccination of ovarian cancer patients with abagovomab - an anti-idiotypic mAb that mimics the ovarian cancer CA125 protein - failed to demonstrate efficacy in the phase III trial named MIMOSA (NCT00418574). We postulated that in this trial patients with a more robust immune system did respond to abagovomab but went undetected among a larger number of non-responders. We also postulated that assessment of the immune system status ahead of abagovomab administration might predict patients' propensity to respond to abagovomab...
September 14, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28918539/accelerating-vaccine-development-during-the-2013-2016-west-african-ebola-virus-disease-outbreak
#9
Elizabeth S Higgs, Sheri A Dubey, Beth A G Coller, Jakub K Simon, Laura Bollinger, Robert A Sorenson, Barthalomew Wilson, Martha C Nason, Lisa E Hensley
The Ebola virus disease outbreak that began in Western Africa in December 2013 was unprecedented in both scope and spread, and the global response was slower and less coherent than was optimal given the scale and pace of the epidemic. Past experience with limited localized outbreaks, lack of licensed medical countermeasures, reluctance by first responders to direct scarce resources to clinical research, community resistance to outside interventions, and lack of local infrastructure were among the factors delaying clinical research during the outbreak...
September 17, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28916989/comparison-of-the-recovery-profile-between-desflurane-and-sevoflurane-in-patients-undergoing-bariatric-surgery-a-meta-analysis-of-randomized-controlled-trials
#10
REVIEW
Preet Mohinder Singh, Anuradha Borle, Jason McGavin, Anjan Trikha, Ashish Sinha
Early and clear recovery from anesthesia is the crux for preventing perioperative complications in the obese undergoing bariatric surgery. Volatile inhalation agents by virtue of high lipid solubility are expected to produce residual anesthetic effects. Prospective randomized trials comparing desflurane and sevoflurane used for anesthesia maintenance (electroencephalograph guided) during bariatric surgery published till 1st of July 2017 were searched in the medical database. Comparisons were made for surrogate markers of recovery from anesthesia that included time to eye-opening (TEo), time to tracheal-extubation (TEx), and Aldrete scores on immediately shifting to recovery (Ald-I)...
September 16, 2017: Obesity Surgery
https://www.readbyqxmd.com/read/28916391/zika-virus-structural-biology-and-progress-in-vaccine-development
#11
REVIEW
Hsiao-Han Lin, Bak-Sau Yip, Li-Min Huang, Suh-Chin Wu
The growing number of zika virus (ZIKV) infections plus a 20-fold increase in neonatal microcephaly in newborns in Brazil have raised alarms in many countries regarding the threat to pregnant women. Instances of microcephaly and central nervous system malformations continue to increase in ZIKV outbreak regions. ZIKV is a small enveloped positive-strand RNA virus belonging to the Flavivirus genus of the Flaviviridae family. High-resolution ZIKV structures recently identified by cryo-electron microscopy indicate that the overall ZIKV structure is similar to those of other flaviviruses...
September 12, 2017: Biotechnology Advances
https://www.readbyqxmd.com/read/28916367/rucaparib-maintenance-treatment-for-recurrent-ovarian-carcinoma-after-response-to-platinum-therapy-ariel3-a-randomised-double-blind-placebo-controlled-phase-3-trial
#12
Robert L Coleman, Amit M Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W Holloway, Margarita Amenedo Gancedo, Peter C Fong, Jeffrey C Goh, David M O'Malley, Deborah K Armstrong, Jesus Garcia-Donas, Elizabeth M Swisher, Anne Floquet, Gottfried E Konecny, Iain A McNeish, Clare L Scott, Terri Cameron, Lara Maloney, Jeff Isaacson, Sandra Goble, Caroline Grace, Thomas C Harding, Mitch Raponi, James Sun, Kevin K Lin, Heidi Giordano, Jonathan A Ledermann
BACKGROUND: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries...
September 12, 2017: Lancet
https://www.readbyqxmd.com/read/28916304/rationale-and-design-of-the-arrest-trial-investigating-mesenchymal-stem-cells-in-the-treatment-of-small-aaa
#13
S Keisin Wang, Linden A Green, Ashley R Gutwein, Natalie A Drucker, Raghu L Motaganahalli, Andres Fajardo, Clifford C Babbey, Michael P Murphy
BACKGROUND: Abdominal aortic aneurysms (AAA) are a major source of morbidity and mortality despite continuing advances in surgical technique and care. Although the inciting factors for AAA development continue to be elusive, accumulating evidence suggests a significant peri-aortic inflammatory response leading to degradation and dilation of the aortic wall. Previous human trials have demonstrated safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of inflammation-related pathologies such as rheumatoid arthritis, graft vs host disease, and transplant rejection...
September 12, 2017: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/28915085/pooled-analysis-safety-profile-of-nivolumab-and-ipilimumab-combination-therapy-in-patients-with-advanced-melanoma
#14
Mario Sznol, Pier Francesco Ferrucci, David Hogg, Michael B Atkins, Pascal Wolter, Massimo Guidoboni, Celeste Lebbé, John M Kirkwood, Jacob Schachter, Gregory A Daniels, Jessica Hassel, Jonathan Cebon, Winald Gerritsen, Victoria Atkinson, Luc Thomas, John McCaffrey, Derek Power, Dana Walker, Rafia Bhore, Joel Jiang, F Stephen Hodi, Jedd D Wolchok
Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management...
September 15, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28914976/haloperidol-versus-5-ht3-receptor-antagonists-for-postoperative-vomiting-and-qtc-prolongation-a-noninferiority-meta-analysis-and-trial-sequential-analysis-of-randomized-controlled-trials
#15
REVIEW
Preet Mohinder Singh, Anuradha Borle, Jeetinder Kaur Makkar, Anjan Trikha, David Fish, Ashish Sinha
Haloperidol is an antipsychotic with well-known antiemetic potential. It is underutilized for postoperative nausea vomiting due to reported corrected QT interval (QTc) prolongation. This meta-analysis evaluates its safety and efficacy as an antiemetic in the perioperative period. Trials comparing haloperidol to 5-HT3 -receptor antagonists (5-HT3 -RA) for 24 postoperative vomiting incidences published up to May 2017 were searched in the medical database. Comparisons were made for antiemetic efficiency variables (vomiting incidence, rescue antiemetic need, and patients with complete response) during early (until 6 hours) and late postoperative phases...
September 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28914666/the-regulation-and-importance-of-monocyte-chemoattractant-protein-1
#16
Vanessa Bianconi, Amirhossein Sahebkar, Stephen L Atkin, Matteo Pirro
PURPOSE OF REVIEW: Monocyte chemoattractant protein (MCP)-1, a chemokine regulating monocyte chemotaxis and T-lymphocyte differentiation by binding to the CC chemokine receptor 2 (CCR2), plays a crucial role in the pathogenesis of inflammatory diseases, atherosclerosis and cancer. This review summarizes the current knowledge on the regulation and importance of the MCP-1/CCR2 axis, focusing on the therapeutic potential of its inhibition. RECENT FINDINGS: Differential modulation of MCP-1 and CCR2 lead to downstream activation pathways, pathogenetic to differing disease conditions characterized by dysregulated monocyte/macrophage tissue recruitment...
September 13, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28914260/high-dose-methotrexate-therapy-significantly-improved-survival-of-adult-acute-lymphoblastic-leukemia-a-phase-iii-study-by-jalsg
#17
T Sakura, F Hayakawa, I Sugiura, T Murayama, K Imai, N Usui, S Fujisawa, T Yamauchi, T Yujiri, K Kakihana, Y Ito, H Kanamori, Y Ueda, Y Miyata, M Kurokawa, N Asou, K Ohnishi, S Ohtake, Y Kobayashi, K Matsuo, H Kiyoi, Y Miyazaki, T Naoe
High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled...
September 15, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28911922/neoadjuvant-sorafenib-gemcitabine-and-cisplatin-administration-preceding-cystectomy-in-patients-with-muscle-invasive-urothelial-bladder-carcinoma-an-open-label-single-arm-single-center-phase-2-study
#18
Andrea Necchi, Salvatore Lo Vullo, Daniele Raggi, Federica Perrone, Patrizia Giannatempo, Giuseppina Calareso, Elena Togliardi, Nicola Nicolai, Luigi Piva, Davide Biasoni, Mario Catanzaro, Tullio Torelli, Silvia Stagni, Maurizio Colecchia, Adele Busico, Marzia Pennati, Nadia Zaffaroni, Luigi Mariani, Roberto Salvioni
BACKGROUND: Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). PATIENTS AND METHODS: After transurethral resection of the bladder, T2-T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400mg q12h daily, continuously, was added to standard GC chemotherapy...
September 11, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28911092/concurrent-and-sequential-initiation-of-ovarian-function-suppression-with-chemotherapy-in-premenopausal-women-with-endocrine-responsive-early-breast-cancer-an-exploratory-analysis-of-text-and-soft
#19
M M Regan, B A Walley, P A Francis, G F Fleming, I Láng, H L Gómez, M Colleoni, C Tondini, G Pinotti, M Salim, S Spazzapan, V Parmar, T Ruhstaller, E A Abdi, R D Gelber, A S Coates, A Goldhirsch, O Pagani
Background: Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. Design and methods: We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28911091/a-phase-iii-trial-comparing-oral-s-1-cisplatin-and-intravenous-5-fluorouracil-cisplatin-in-patients-with-untreated-diffuse-gastric-cancer
#20
J A Ajani, M Abramov, I Bondarenko, Y Shparyk, V Gorbunova, A Hontsa, N Otchenash, M Alsina, S Lazarev, J Feliu, A Elme, V Esko, K Abdalla, U Verma, F Benedetti, T Aoyama, H Mizuguchi, L Makris, G Rosati
Background: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. Patients and methods: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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