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https://www.readbyqxmd.com/read/28340333/the-randomized-crm-an-approach-to-overcoming-the-long-memory-property-of-the-crm
#1
Joseph S Koopmeiners, Andrew Wey
The primary object of a Phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose-escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose finding. Recently, it was shown that the CRM has a tendency to get "stuck" on a dose level, with little escalation or de-escalation in the late stages of the trial, due to the long-memory property of the CRM...
March 1, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28331050/first-in-human-clinical-trial-of-oral-onc201-in-patients-with-refractory-solid-tumors
#2
Mark N Stein, Joseph R Bertino, Howard L Kaufman, Tina Mayer, Rebecca Moss, Ann Silk, Nancy Chan, Jyoti Malhotra, Lorna Rodriguez-Rodriguez, Joseph Aisner, Robert D Aiken, Bruce G Haffty, Robert S DiPaola, Tracie Saunders, Andrew Zloza, Sherri Damare, Yasmeen Beckett, Bangning Yu, Saltanat Najmi, Christian Gabel, Siobhan Dickerson, Ling Zheng, Wafik S El-Deiry, Joshua Allen, Martin Stogniew, Wolfgang Oster, Janice M Mehnert
Purpose ONC201 is a small molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design This open-label study treated 10 patients during dose escalation with histologically-confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design...
March 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28331003/phase-i-dose-escalation-study-of-taselisib-gdc-0032-an-oral-pi3k-inhibitor-in-patients-with-advanced-solid-tumors
#3
Dejan Juric, Ian Krop, Ramesh K Ramanathan, Timothy R Wilson, Joseph A Ware, Sandra Sanabria Bohorquez, Heidi Savage, Deepak Sampath, Laurent Salphati, Ray Lin, Huan Jin, Hema Parmar, Jerry Y Hsu, Daniel D Von Hoff, José Baselga
Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window...
March 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28328624/long-term-maintenance-of-clinical-endoscopic-and-radiographic-response-to-ustekinumab-in-moderate-to-severe-crohn-s-disease-real-world-experience-from-a-multicenter-cohort-study
#4
Christopher Ma, Richard N Fedorak, Gilaad G Kaplan, Levinus A Dieleman, Shane M Devlin, Nathan Stern, Karen I Kroeker, Cynthia H Seow, Yvette Leung, Kerri L Novak, Brendan P Halloran, Vivian W Huang, Karen Wong, Philip K Blustein, Subrata Ghosh, Remo Panaccione
BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukins 12 and 23. While effective in clinical trials for Crohn's disease (CD), long-term maintenance of response in the real-world setting is unclear. We aim to assess the efficacy of ustekinumab for maintaining clinical, endoscopic, and radiographic response in CD. METHODS: A retrospective multicenter cohort study was performed on patients with CD achieving steroid-free clinical response to ustekinumab induction, and advanced onto a regularly scheduled maintenance ustekinumab regimen between 2011 and 2016...
March 21, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28327089/uniform-fdg-pet-guided-gradient-dose-prescription-to-reduce-late-radiation-toxicity-upgrade-rt-study-protocol-for-a-randomized-clinical-trial-with-dose-reduction-to-the-elective-neck-in-head-and-neck-squamous-cell-carcinoma
#5
Sven van den Bosch, Tim Dijkema, Martina C Kunze-Busch, Chris H J Terhaard, Cornelis P J Raaijmakers, Patricia A H Doornaert, Frank J P Hoebers, Marije R Vergeer, Bas Kreike, Oda B Wijers, Wim J G Oyen, Johannes H A M Kaanders
BACKGROUND: In definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called 'elective dose' in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary. Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment...
March 21, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28326356/effect-of-four-monthly-doses-of-a-human-monoclonal-anti-fgf23-antibody-krn23-on-quality-of-life-in-x-linked-hypophosphatemia
#6
Mary D Ruppe, Xiaoping Zhang, Erik A Imel, Thomas J Weber, Mark A Klausner, Takahiro Ito, Maria Vergeire, Jeffrey S Humphrey, Francis H Glorieux, Anthony A Portale, Karl Insogna, Munro Peacock, Thomas O Carpenter
X-linked hypophosphatemia (XLH) is characterized by lower extremity deformities that lead to bone and/or joint pain that result from decreased renal tubular reabsorption leading to hypophosphatemia caused by elevated levels of fibroblast growth factor 23 (FGF23). OBJECTIVE: Validate the use of SF-36v2 Health Survey (SF-36v2) and the Western Ontario and McMaster Osteoarthritis Index (WOMAC) to measure previously unstudied health-related quality of life (HRQoL) in XLH patients and determine the change in HRQoL before and after treatment with KRN23, a human monoclonal anti-FGF23 antibody...
December 2016: Bone Reports
https://www.readbyqxmd.com/read/28324749/a-phase-i-study-of-sar405838-a-novel-human-double-minute-2-hdm2-antagonist-in-patients-with-solid-tumours
#7
Maja de Jonge, Vincent A de Weger, Mark A Dickson, Marlies Langenberg, Axel Le Cesne, Andrew J Wagner, Karl Hsu, Wei Zheng, Sandrine Macé, Gilles Tuffal, Koruth Thomas, Jan H M Schellens
PURPOSE: In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479). METHODS: In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible...
March 16, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28324671/dose-de-escalation-of-intrapleural-tissue-plasminogen-activator-therapy-for-pleural-infection-the-adapt-project
#8
Natalia Popowicz, Oliver Bintcliffe, Duneesha De Fonseka, Kevin G Blyth, Nicola A Smith, Francesco Piccolo, Geoffrey Martin, Donny Wong, Anthony Edey, Nick Maskell, Y C Gary Lee
RATIONALE: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10mg and deoxyribonuclease (DNase) 5mg administered twice daily has been shown in randomized and open-label studies to enable adequate drainage of over 90% of infected pleural effusions without surgery. Potential bleeding risks associated with intrapleural tPA and the drug costs remain important concerns. The ongoing ADAPT (Alteplase Dose Assessment for Pleural infection Therapy) project aims to investigate the efficacy and safety of dose de-escalation for intrapleural tPA...
March 21, 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/28322590/randomized-clinical-trials-of-gene-transfer-for-heart-failure-with-reduced-ejection-fraction
#9
William F Penny, H Kirk Hammond
Despite improvement in drug and device therapy for heart failure, hospitalization rates and mortality have changed little in the past decade. Randomized clinical trials using gene transfer to improve function of the failing heart are the focus of this review. Four randomized clinical trials of gene transfer in heart failure with reduced ejection fraction (HFrEF) have been published. Each enrolled patients with stable symptomatic HFrEF and used either intracoronary delivery of a virus vector or endocardial injection of a plasmid (1 trial)...
March 21, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28321612/serial-serum-immunoglobulin-g-igg-trough-levels-in-patients-with-x-linked-agammaglobulinemia-on-replacement-therapy-with-intravenous-immunoglobulin-its-correlation-with-infections-in-indian-children
#10
Deepti Suri, Sagar Bhattad, Avinash Sharma, Anju Gupta, Amit Rawat, Shobha Sehgal, Surjit Singh, Sudhir Gupta
Patients with primary antibody deficiency (PAD) are being increasingly diagnosed in the developing world. However, care of these children continues to remain suboptimal due to financial and social constraints. Immunoglobulin (Ig) trough level is an important predicting factor for infections in children on replacement immunoglobulin therapy. There are no data on this aspect from the developing world. Therefore, we studied serial immunoglobulin G (IgG) trough levels in 14 children with X-linked agammaglobulinemia (XLA) receiving replacement intravenous immunoglobulin (IVIG)...
March 21, 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/28321512/four-year-maintenance-treatment-with-adalimumab-in-japanese-patients-with-moderately-to-severely-active-ulcerative-colitis
#11
Yasuo Suzuki, Satoshi Motoya, Hiroyuki Hanai, Toshifumi Hibi, Shiro Nakamura, Andreas Lazar, Anne Martin Robinson, Martha Skup, Nael Mohamed Mostafa, Bidan Huang, Roopal Thakkar, Mamoru Watanabe
BACKGROUND: The 52-week safety and efficacy of adalimumab in Japanese patients with moderately to severely active ulcerative colitis were demonstrated in a placebo-controlled phase 2/3 trial. Data from patients who enrolled in the open-label extension study are presented. METHODS: Remission and response per the full Mayo score (FMS) and the partial Mayo score (PMS), remission per the Inflammatory Bowel Disease Questionnaire (IBDQ) score, corticosteroid-free remission, and mucosal healing were assessed up to week 196 (week 208 for remission/response per PMS) of adalimumab treatment in patients who received one or more doses of adalimumab with use of a hybrid nonresponder imputation (hNRI) method...
March 20, 2017: Journal of Gastroenterology
https://www.readbyqxmd.com/read/28320635/safety-and-efficacy-of-multipotent-adult-progenitor-cells-in-acute-ischaemic-stroke-masters-a-randomised-double-blind-placebo-controlled-phase-2-trial
#12
David C Hess, Lawrence R Wechsler, Wayne M Clark, Sean I Savitz, Gary A Ford, David Chiu, Dileep R Yavagal, Ken Uchino, David S Liebeskind, Alexander P Auchus, Souvik Sen, Cathy A Sila, Jeffrey D Vest, Robert W Mays
BACKGROUND: Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. METHODS: We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA...
March 17, 2017: Lancet Neurology
https://www.readbyqxmd.com/read/28318812/comparative-study-of-anuvasana-basti-with-constant-and-escalating-dose-as-an-alternative-to-snehapana-in-purvakarma-of-vamana-and-virechana
#13
Priyadarshani Arvind Kadus, Surendra M Vedpathak
Snehapana i.e. internal administration of fat is the essential step prior to Vamana and Virechana (therapeutic vomiting and purgation). But it was found that 10-15% patients has got reluctance towards Snehapana hence may deprive the benefits of Shodhana. These inconveniences made us think about effective alternative to counter drawbacks of Snehapana. On the basis of literary review and pilot study, it was confirmed that, Anuvasana Basti can be administered as an alternative for Snehapana. To evaluate samyak snigdha lakshana i...
March 16, 2017: Journal of Ayurveda and Integrative Medicine
https://www.readbyqxmd.com/read/28317088/phase-i-trial-of-the-oral-smoothened-inhibitor-sonidegib-in-combination-with-paclitaxel-in-patients-with-advanced-solid-tumors
#14
A Stathis, D Hess, R von Moos, K Homicsko, G Griguolo, M Joerger, M Mark, C J Ackermann, S Allegrini, C V Catapano, A Xyrafas, M Enoiu, S Berardi, P Gargiulo, C Sessa
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m(2) on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28315060/results-of-a-phase-ib-trial-of-combination-immunotherapy-with-a-cd8-%C3%A2-t-cell-eliciting-vaccine-and-trastuzumab-in-breast-cancer-patients
#15
G Travis Clifton, Jennifer K Litton, Karen Arrington, Sathibalan Ponniah, Nuhad K Ibrahim, Victor Gall, Gheath Alatrash, George E Peoples, Elizabeth A Mittendorf
BACKGROUND: CD8+ T cell-eliciting vaccines are being investigated in breast cancer patients. Preclinical data showed that trastuzumab increases the susceptibility of tumor cells to lysis by vaccine-generated CD8+ T cells, suggesting potential benefit of a combination immunotherapy strategy. The current trial was undertaken to demonstrate the safety of this approach. METHODS: This study was designed as a dose-escalation trial enrolling clinically disease-free, human leukocyte antigen A2+ or A3+ , human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients...
March 17, 2017: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/28314877/fully-automated-vmat-treatment-planning-for-advanced-stage-nsclc-patients
#16
Giuseppe Della Gala, Maarten L P Dirkx, Nienke Hoekstra, Dennie Fransen, Nico Lanconelli, Marjan van de Pol, Ben J M Heijmen, Steven F Petit
PURPOSE: To develop a fully automated procedure for multicriterial volumetric modulated arc therapy (VMAT) treatment planning (autoVMAT) for stage III/IV non-small cell lung cancer (NSCLC) patients treated with curative intent. MATERIALS AND METHODS: After configuring the developed autoVMAT system for NSCLC, autoVMAT plans were compared with manually generated clinically delivered intensity-modulated radiotherapy (IMRT) plans for 41 patients. AutoVMAT plans were also compared to manually generated VMAT plans in the absence of time pressure...
March 17, 2017: Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft ... [et Al]
https://www.readbyqxmd.com/read/28314838/a-phase-i-study-of-abiraterone-acetate-combined-with-bez235-a-dual-pi3k-mtor-inhibitor-in-metastatic-castration-resistant-prostate-cancer
#17
Xiao X Wei, Andrew C Hsieh, Won Kim, Terence Friedlander, Amy M Lin, Mirela Louttit, Charles J Ryan
LESSONS LEARNED: The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored. BACKGROUND: Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer...
March 17, 2017: Oncologist
https://www.readbyqxmd.com/read/28314788/the-parp-inhibitor-veliparib-can-be-safely-added-to-bendamustine-and-rituximab-and-has-preliminary-evidence-of-activity-in-b-cell-lymphoma
#18
Jacob D Soumerai, Andrew D Zelenetz, Craig Moskowitz, M Lia Palomba, Paul A Hamlin, Ariela Noy, David J Straus, Alison J Moskowitz, Anas Younes, Matthew J Matasar, Steven Horwitz, Carol Portlock, Jason Konner, Mrinal M Gounder, David M Hyman, Martin H Voss, Matthew G Fury, Devika Gajria, Richard D Carvajal, Alan L Ho, Jan H Beumer, Brian Kiesel, Zhigang Zhang, Alice Chen, Richard F Little, Christine Jarjies, Thu O Dang, Fallon France, Nishant Mishra, John F Gerecitano
PURPOSE: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase 1 study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. EXPERIMENTAL DESIGN: This dose-escalation study evaluated safety, pharmacokinetics and preliminary efficacy of veliparib (20-400 mg BID, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 IV, days 1 and 2)...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28314755/a-randomised-controlled-trial-of-the-efficacy-and-safety-of-allopurinol-dose-escalation-to-achieve-target-serum-urate-in-people-with-gout
#19
Lisa K Stamp, Peter T Chapman, Murray L Barclay, Anne Horne, Christopher Frampton, Paul Tan, Jill Drake, Nicola Dalbeth
OBJECTIVES: To determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach. METHODS: A randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at least creatinine clearance (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL were recruited. Participants were randomised to continue current dose (control) or allopurinol dose escalation for 12 months...
March 17, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28306192/histone-deacetylase-activity-mediates-acquired-resistance-towards-structurally-diverse-hsp90-inhibitors
#20
Ryan C Chai, Jessica L Vieusseux, Benjamin J Lang, Chau H Nguyen, Michelle M Kouspou, Kara L Britt, John T Price
Heat Shock Protein 90 (HSP90) regulates multiple signaling pathways critical for tumor growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may the presence of de novo or acquired resistance within the tumors. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-AAG...
March 17, 2017: Molecular Oncology
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