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Dose escalation

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https://www.readbyqxmd.com/read/28550039/a-phase-1-2-study-of-the-oral-proteasome-inhibitor-ixazomib-in-relapsed-or-refractory-light-chain-al-amyloidosis
#1
Vaishali Sanchorawala, Giovanni Palladini, Vishal Kukreti, Jeffrey A Zonder, Adam D Cohen, David C Seldin, Angela Dispenzieri, Arnaud Jaccard, Stefan O Schönland, Deborah Berg, Huyuan Yang, Neeraj Gupta, Ai-Min Hui, Raymond L Comenzo, Giampaolo Merlini
This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory AL amyloidosis (RRAL). Ixazomib was administered to adult patients with RRAL after ≥1 prior line of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naïve and PI-exposed patients) at the maximum tolerated dose (MTD)...
May 26, 2017: Blood
https://www.readbyqxmd.com/read/28548028/developmental-differences-between-newborn-and-adult-mice-in-response-to-romiplostim
#2
Katherine A Sparger, Haley Ramsey, Viola Lorenz, Zhi-Jian Liu, Henry A Feldman, Nan Li, Tahirih Laforest, Martha C Sola-Visner
Thrombocytopenia is frequent among sick neonates. While most cases are transient, some neonates experience prolonged and severe thrombocytopenia. These infants often pose diagnostic and therapeutic challenges, and may receive large numbers of platelet transfusions. Romiplostim (ROM) is a thrombopoietin (TPO)-receptor-agonist approved for treatment of adults with chronic immune thrombocytopenia (ITP). The immature platelet fraction (IPF) is a novel measure of newly produced platelets, which could aid with the diagnostic evaluation of thrombocytopenic neonates...
May 26, 2017: Platelets
https://www.readbyqxmd.com/read/28546227/keyboard-a-novel-bayesian-toxicity-probability-interval-design-for-phase-i-clinical-trials
#3
Fangrong Yan, Sumithra J Mandrekar, Ying Yuan
The primary objective of phase I oncology trials is to find the maximum tolerated dose (MTD). The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval...
May 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28545679/selective-use-of-radioactive-iodine-rai-in-thyroid-cancer-no-longer-one-size-fits-all
#4
REVIEW
J L Marti, L G T Morris, A S Ho
A remarkable, evidence-based trend toward de-escalation has reformed the practice of radioactive iodine (RAI) administration for thyroid cancer patients. Updated guidelines have supported both decreased RAI doses for select populations, as well as expanded definitions of low-risk and intermediate-risk patients that may not require RAI. Correspondingly, there is now increased flexibility for hemithyroidectomy without need for RAI, and relaxed TSH suppression targets for low-risk thyroidectomy patients. Clinical judgment remains indispensable where multiple risk factors co-exist that individually are not indications for RAI...
May 3, 2017: European Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28544774/safety-pharmacokinetics-and-pharmacodynamics-of-hetrombopag-olamine-a-novel-tpo-r-agonist-in-healthy-subjects
#5
Li Zheng, Mao-Zhi Liang, Xiao-Ling Zeng, Cai-Zheng Li, Yi-Fan Zhang, Xiao-Yan Chen, Xi Zhu, An-Bo Xiang
Hetrombopag olamine (hetrombopag) is a novel small-molecule, orally bioavailable, non-peptide thrombopoietin (TPO) receptor agonist that is being developed as the treatment for thrombocytopenia. Two randomized, placebo-controlled phase I studies were conducted in 72 healthy subjects to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of hetrombopag. Hetrombopag was orally administered with a single dose in 5 dose cohorts (5 mg, 10 mg, 20 mg, 30 mg or 40 mg) in the first study, and given once daily for 10 days in 3 dose cohorts (2...
May 24, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28542711/preventing-relapse-after-haematopoietic-stem-cell-transplantation-for-acute-leukaemia-the-role-of-post-transplantation-minimal-residual-disease-mrd-monitoring-and-mrd-directed-intervention
#6
REVIEW
Xiao-Dong Mo, Meng Lv, Xiao-Jun Huang
Relapse is the main cause of treatment failure after allogeneic haematopoietic stem cell transplantation (allo-HSCT) for acute leukaemia (AL). Post-transplantation minimal residual disease (MRD) monitoring enables risk stratification and identifies AL patients at higher risk of relapse. MRD assessment primarily involves the determination of leukaemia-associated immunophenotypic patterns using multiparameter flow cytometry, and the polymerase chain reaction (PCR)-based evaluation of expression levels of leukaemia-related genes (specific reciprocal gene rearrangements and other mutation types)...
May 23, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28541431/emerging-safety-of-intramedullary-transplantation-of-human-neural-stem-cells-in-chronic-cervical-and-thoracic-spinal-cord-injury
#7
Allan D Levi, David O Okonkwo, Paul Park, Arthur L Jenkins, Shekar N Kurpad, Ann M Parr, Aruna Ganju, Bizhan Aarabi, Dong Kim, Steven Casha, Michael G Fehlings, James S Harrop, Kim D Anderson, Allyson Gage, Jane Hsieh, Stephen Huhn, Armin Curt, Raphael Guzman
BACKGROUND: Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). OBJECTIVE: To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. METHODS: Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI...
May 24, 2017: Neurosurgery
https://www.readbyqxmd.com/read/28540172/nonlinear-relationship-between-enteric-coated-mycophenolate-sodium-dose-and-mycophenolic-acid-exposure-in-han-kidney-transplantation-recipients
#8
Jun Zhang, Mengmeng Jia, Lihua Zuo, Na Li, Yonggang Luo, Zhi Sun, Xiaojian Zhang, Zhenfeng Zhu
The aim of the research was to investigate the pharmacokinetics (PK) of enteric-coated mycophenolate sodium (EC-MPS) by quantification of the active metabolite of mycophenolic acid (MPA) after multiple escalating oral doses in Han kidney transplant recipients. A total of 28 Han postoperative kidney transplant recipients were given a multiple-dose of 540, 720 or 900 mg of EC-MPS two times a day in combination with tacrolimus for 6 days. Blood specimens were collected at each time point from 0 to 12 h after EC-MPS administration...
May 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/28539888/safety-and-immunogenicity-of-a-human-epidermal-growth-factor-receptor-1-her1-based-vaccine-in-prostate-castration-resistant-carcinoma-patients-a-dose-escalation-phase-i-study-trial
#9
Iraida Caballero, Lazaro E Aira, Anabel Lavastida, Xitlally Popa, Javier Rivero, Joaquín González, Mónica Mesa, Narjara González, Kelly Coba, Patricia Lorenzo-Luaces, Barbara Wilkinson, Yuliannis Santiesteban, Yanela Santiesteban, Mayelin Troche, Eduardo Suarez, Tania Crombet, Belinda Sánchez, Angel Casacó, Amparo Macías, Zaima Mazorra
Metastatic castration-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Activation of the human epidermal growth factor receptor 1 (HER1) in prostate cancer contributes to metastatic progression as well as to disease relapse. Here, we determined the toxicity and immunogenicity of a HER1-based cancer vaccine in CRPC patients included in a phase I clinical trial. CRPC patients (n = 24) were intramuscularly vaccinated with HER1 vaccine consisting of the extracellular domain of HER1 molecule (ECD) and very small size proteoliposome from Neisseria meningitidis (VSSP) and Montanide ISA-51 VG as adjuvants...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28539464/phase-ib-pilot-study-to-evaluate-reparixin-in-combination-with-weekly-paclitaxel-in-patients-with-her-2-negative-metastatic-breast-cancer-mbc
#10
Anne F Schott, Lori Goldstein, Massimo Cristofanilli, Pier Adelchi Ruffini, Susan McCanna, James M Reuben, Raymond Perez, Giraldo Kato, Max S Wicha
CXCR1 is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSC). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSC in human breast cancer xenografts. This Phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in metastatic breast cancer (MBC) patients (Trial registration ID: NCT02001974). <p>Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy...
May 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28537808/dose-intense-dose-dense-and-tailored-dose-adjuvant-chemotherapy-for-early-breast-cancer-an-evolution-of-concepts
#11
Alexios Matikas, Theodoros Foukakis, Jonas Bergh
BACKGROUND: The introduction of adjuvant chemotherapy following surgery for early breast cancer (BC) and its integration into routine clinical practice has consistently improved clinical outcomes. Since the addition of other agents to the contemporary standard of care containing an anthracycline, cyclophosphamide and a taxane has not lead to further prolongation of survival, subsequent efforts concentrated on escalating the administered doses and reducing the time interval between chemotherapy cycles...
May 24, 2017: Acta Oncologica
https://www.readbyqxmd.com/read/28537467/dose-escalation-of-biologics-in-crohn-s-disease-critical-review-of-observational-studies
#12
Thomas R Einarson, Basil G Bereza, Xin Ying Lee, Filippo Lelli
BACKGROUND: Biologics used to treat Crohn's disease (CD) may lose their effect over time, requiring dose escalation. Little information is available on this topic. AIM: To summarize rates of dose escalation, duration, de-escalation in observational studies of CD in adults treated with adalimumab, infliximab, and vedolizumab in Europe. METHODS: Two independent investigators searched Medline and Embase for observational studies published 1998-2015 and proceedings from 4 major scientific meetings...
May 24, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28535657/-safety-and-efficacy-of-infusional-fluorouracil-leucovorin-oxaliplatin-and-irinotecan-folfoxiri-in-chinese-patients-with-advanced-colorectal-cancer
#13
Y Song, W W Li, J Huang
Objective: To establish the maximum tolerated dose (MTD) of 5-fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI), and to evaluate the safety and efficacy in Chinese patients with advanced colorectal cancer. Methods: Patients were treated with a regimen consisting of infusional 5-fluorouracil (2 400 mg/m(2) on day 1), leucovorin (200 mg/m(2) on day 1), oxaliplatin (85 mg/m(2) on day 1), and irinotecan (at doses from 150 to 180 mg/m(2) on day 8) according to the dose-escalation schema. Treatment was repeated every 14 days...
May 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28535569/reinstituting-the-bolus-new-reasoning-for-an-existing-technique
#14
Porter W McRoberts, Jason E Pope, Catalina Apostol
Improved intrathecal (IT) pump technology is increasing the accuracy of IT opioid bolus dosing and promising advances in pain therapy. Opioid bolus dosing can be used with a minimal continuous infusion or it can function as the sole therapy. Bolus-only dosing is characterized by minimal use of opioid (often less than 1 mg of IT morphine). It achieves adequate pain control while reducing tolerance and possibly opioid-induced hyperalgesia. It may prevent receptor saturation, and provide a "washing out" of the opioid receptor that prevents the observed dose escalation resulting from continuous infusions...
May 2017: Pain Physician
https://www.readbyqxmd.com/read/28533941/changes-in-clinical-laboratory-parameters-and-pharmacodynamic-markers-in-response-to-blinatumomab-treatment-of-patients-with-relapsed-refractory-all
#15
Virginie Nägele, Andrea Kratzer, Gerhard Zugmaier, Chris Holland, Youssef Hijazi, Max S Topp, Nicola Gökbuget, Patrick A Baeuerle, Peter Kufer, Andreas Wolf, Matthias Klinger
BACKGROUND: Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We evaluated changes in laboratory parameters and immunopharmacodynamic markers in patients who received blinatumomab in the exploratory phase II study. METHODS: Data from 36 adults with relapsed/refractory ALL receiving blinatumomab as 4-week continuous IV infusions in various dose cohorts were analyzed for changes in liver enzymes, first-dose parameters, peripheral blood cell subpopulations, and cytokine/granzyme B release...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28531881/first-in-man-dose-escalation-and-pharmacokinetic-study-of-cap7-1-a-novel-prodrug-of-etoposide-in-adults-with-refractory-solid-tumours
#16
U Keilholz, L Rohde, P Mehlitz, M Knoedler, A Schmittel, V Kümmerlen, K Klinghammer, P Treasure, M Lassus, G Steventon, M Machacek, N Utku
AIM: An open-label, phase I dose-escalation trial was performed in adult patients with various solid cancers to identify the maximum tolerated dose (MTD), to assess the safety, pharmacokinetic profile and anti-tumour activity of the new prodrug CAP7.1. The prodrug is converted to its active moiety etoposide via carboxylesterases in selective cells leading to a better tolerability and higher efficacy in therapeutic resistance cells and children with refractory neuroblastoma. PATIENTS AND METHODS: Eligible adult patients with advanced, refractory, solid malignancies received CAP7...
May 19, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28529896/advances-in-radiotherapy-techniques-and-delivery-for-non-small-cell-lung-cancer-benefits-of-intensity-modulated-radiation-therapy-proton-therapy-and-stereotactic-body-radiation-therapy
#17
REVIEW
Tejan P Diwanji, Pranshu Mohindra, Melissa Vyfhuis, James W Snider, Chaitanya Kalavagunta, Sina Mossahebi, Jen Yu, Steven Feigenberg, Shahed N Badiyan
The 21st century has seen several paradigm shifts in the treatment of non-small cell lung cancer (NSCLC) in early-stage inoperable disease, definitive locally advanced disease, and the postoperative setting. A key driver in improvement of local disease control has been the significant evolution of radiation therapy techniques in the last three decades, allowing for delivery of definitive radiation doses while limiting exposure of normal tissues. For patients with locally-advanced NSCLC, the advent of volumetric imaging techniques has allowed a shift from 2-dimensional approaches to 3-dimensional conformal radiation therapy (3DCRT)...
April 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28529840/adoptive-cell-therapy-with-tregs-to-improve-transplant-outcomes-the-promise-and-the-stumbling-blocks
#18
Mohamed B Ezzelarab, Angus W Thomson
The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety...
December 2016: Current Transplantation Reports
https://www.readbyqxmd.com/read/28528705/complications-of-proton-pump-inhibitor-therapy
#19
REVIEW
Michael F Vaezi, Yu-Xiao Yang, Colin W Howden
Safety issues associated with proton pump inhibitors (PPIs) have recently attracted widespread media and lay attention. Gastroenterologists are frequently asked about the appropriateness of PPI therapy for specific patients. Furthermore, some patients may have had PPI therapy discontinued abruptly or inappropriately due to safety concerns. Faced with such a wide variety of potentially serious adverse consequences, prescribers need to evaluate the evidence objectively to discern the likelihood that any reported association might actually be causal...
May 18, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28526920/effects-of-semaglutide-on-beta-cell-function-and-glycaemic-control-in-participants-with-type-2-diabetes-a-randomised-double-blind-placebo-controlled-trial
#20
Christoph Kapitza, Kirsten Dahl, Jacob B Jacobsen, Mads B Axelsen, Anne Flint
AIMS/HYPOTHESIS: Semaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed. METHODS: In this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18-64 years) participants with type 2 diabetes (eligibility: HbA1c of 6...
May 19, 2017: Diabetologia
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