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Proof of concept Phase I or Phase II clinic trial

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https://www.readbyqxmd.com/read/27883925/factors-associated-with-failure-of-oncology-drugs-in-late-stage-clinical-development-a-systematic-review
#1
REVIEW
Denis L Jardim, Eric S Groves, Philip P Breitfeld, Razelle Kurzrock
BACKGROUND: We aimed to describe the reasons for failure of experimental anticancer drugs in late-stage clinical development. MATERIAL AND METHODS: We searched the PharmaProjects database (https://citeline.com/products/pharmaprojects/) for anticancer drugs discontinued between 01/01/2009 and 06/30/2014. Drug programs that reached phase III trials, but never gained Food and Drug Administration (FDA) approval were compared to 37 anti-cancer drugs achieving FDA approval in this time period...
November 4, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27663483/pharmacodynamic-endpoints-as-clinical-trial-objectives-to-answer-important-questions-in-oncology-drug-development
#2
Ralph E Parchment, James H Doroshow
Analyzing the molecular interplay between malignancies and therapeutic agents is rarely a straightforward process, but we hope that this special issue of Seminars has highlighted the clinical value of such endeavors as well as the relevant theoretical and practical considerations. Here, we conclude with both an overview of the various high-value applications of clinical pharmacodynamics (PD) in developmental therapeutics and an outline of the framework for incorporating PD analyses into the design of clinical trials...
August 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/27596486/embalance-validation-of-a-decision-support-system-in-the-early-diagnostic-evaluation-and-management-plan-formulation-of-balance-disorders-in-primary-care-study-protocol-of-a-feasibility-randomised-controlled-trial
#3
Laura Rammazzo, Dimitris Kikidis, Amal Anwer, Nora Macdonald, Efthymios Kyrodimos, Christoph Maurer, Floris Wuyts, Linda Luxon, Athanasios Bibas, Doris-Eva Bamiou
BACKGROUND: Balance problems are caused by multiple factors and often lead to falls and related fractures, bringing large socio-economic costs. The complexity of balance control mechanisms, the lack of medical expertise, and the absence of specialised equipment contribute to the delayed or incorrect diagnosis and management ofthese patients. Advances in computer science have allowed the development of computer systems that support clinical diagnosis and treatment decisions based on individualised patient data...
2016: Trials
https://www.readbyqxmd.com/read/27539973/time-to-give-up-on-cardioprotection-a-critical-appraisal-of-clinical-studies-on-ischemic-pre-post-and-remote-conditioning
#4
REVIEW
Gerd Heusch, Tienush Rassaf
The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of post-myocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin...
August 19, 2016: Circulation Research
https://www.readbyqxmd.com/read/27521810/design-rationale-and-baseline-characteristics-of-the-randomized-double-blind-phase-ii-clinical-trial-of-ibudilast-in-progressive-multiple-sclerosis
#5
Robert J Fox, Christopher S Coffey, Merit E Cudkowicz, Trevis Gleason, Andrew Goodman, Eric C Klawiter, Kazuko Matsuda, Michelle McGovern, Robin Conwit, Robert Naismith, Akshata Ashokkumar, Robert Bermel, Dixie Ecklund, Maxine Koepp, Jeffrey Long, Sneha Natarajan, Srividya Ramachandran, Thomai Skaramagas, Brenda Thornell, Jon Yankey, Mark Agius, Khurram Bashir, Bruce Cohen, Patricia Coyle, Silvia Delgado, Dana Dewitt, Angela Flores, Barbara Giesser, Myla Goldman, Burk Jubelt, Neil Lava, Sharon Lynch, Augusto Miravalle, Harold Moses, Daniel Ontaneda, Jai Perumal, Michael Racke, Pavle Repovic, Claire Riley, Christopher Severson, Shlomo Shinnar, Valerie Suski, Bianca Weinstock-Gutman, Vijayshree Yadav, Aram Zabeti
BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties...
September 2016: Contemporary Clinical Trials
https://www.readbyqxmd.com/read/27354810/pazopanib-in-the-management-of-advanced-soft-tissue-sarcomas
#6
REVIEW
Lee D Cranmer, Elizabeth T Loggers, Seth M Pollack
Therapy of soft tissue sarcomas represents an area of significant unmet need in oncology. Angiogenesis has been explored as a potential target both preclinically and clinically, with suggestions of activity. Pazopanib is a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects. In a Phase II study, pazopanib demonstrated activity in strata enrolling patients with leiomyosarcomas, synovial sarcomas, or other sarcomas but not those enrolling adipocytic sarcomas. PALETTE, the pivotal Phase III trial, demonstrated improved progression-free survival versus placebo in pazopanib-treated patients previously treated for advanced soft tissue sarcomas...
2016: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/27284065/treatment-of-metastatic-renal-cell-carcinoma-mrcc-with-caix-car-engineered-t-cells-a-completed-study-overview
#7
REVIEW
Cor H J Lamers, Yarne Klaver, Jan W Gratama, Stefan Sleijfer, Reno Debets
We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment...
June 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27171154/free-fatty-acid-receptor-agonists-for-the-treatment-of-type-2-diabetes-drugs-in-preclinical-to-phase-ii-clinical-development
#8
Zheng Li, Qianqian Qiu, Xinqian Geng, Jianyong Yang, Wenlong Huang, Hai Qian
INTRODUCTION: The alarming prevalence of type 2 diabetes mellitus (T2DM) stimulated the exploitation of new antidiabetic drugs with extended durability and enhanced safety. In this regard, the free fatty acid receptor 1 (FFA1) and FFA4 have emerged as attractive targets in the last decade. FFA1 has prominent advantages in promoting insulin and incretin secretion while FFA4 shows great potential in incretin secretion, insulin sensitization and anti-inflammatory effects. AREA COVERED: Herein, the authors focus specifically on FFA1 and FFA4 agonists in clinical trials and preclinical development...
August 2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27043241/treatment-of-cmv-infection-after-allogeneic-hematopoietic-stem-cell-transplantation
#9
Enrico Maffini, Luisa Giaccone, Moreno Festuccia, Lucia Brunello, Alessandro Busca, Benedetto Bruno
Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials...
June 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27035618/a-novel-treatment-of-cystic-fibrosis-acting-on-target-cysteamine-plus-epigallocatechin-gallate-for-the-autophagy-dependent-rescue-of-class-ii-mutated-cftr
#10
A Tosco, F De Gregorio, S Esposito, D De Stefano, I Sana, E Ferrari, A Sepe, L Salvadori, P Buonpensiero, A Di Pasqua, R Grassia, C A Leone, S Guido, G De Rosa, S Lusa, G Bona, G Stoll, M C Maiuri, A Mehta, G Kroemer, L Maiuri, V Raia
We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent...
August 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27000960/equal-access-to-innovative-therapies-and-precision-cancer-care
#11
REVIEW
Agnès Buzyn, Jean-Yves Blay, Natalie Hoog-Labouret, Marta Jimenez, Frédérique Nowak, Marie-Cécile Le Deley, David Pérol, Christian Cailliot, Jacques Raynaud, Gilles Vassal
Patients with cancers of differing histologies that express certain biomarkers are likely to benefit from treatment with targeted therapies. However, targets can be present in malignancies other than those indicated by a drug's label, and as a result, affected patients will have no access to those potentially useful drugs. To tackle this issue, the French National Cancer Institute developed the AcSé Programme in 2013. This programme is designed to make treatment decisions or recommendations on the basis of the presence of relevant biomarkers for malignancies with no targeted therapies available and also aims to improve safety, and evaluate the efficacy of targeted drugs used outside of their approved indications...
June 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27000881/translational-hurdles-in-stroke-recovery-studies
#12
Jukka Jolkkonen, Gert Kwakkel
Emerging understanding of brain plasticity has opened new avenues for the treatment of stroke. The promising preclinical evidence with neuroprotective drugs has not been confirmed in clinical trials, thus nowadays, researchers, pharmaceutical companies, and funding bodies hesitate to initiate these expensive trials with restorative therapies. Since many of the previous failures can be traced to low study quality, a number of guidelines such as STAIR and STEPS were introduced to rectify these shortcomings. However, these guidelines stem from the study design for neuroprotective drugs and one may question whether they are appropriate for restorative approaches, which rely heavily on behavioral testing...
August 2016: Translational Stroke Research
https://www.readbyqxmd.com/read/26983031/a-proof-of-concept-phase-ii-randomized-european-trial-on-the-efficacy-of-alf-5755-a-novel-extracellular-matrix-targeted-antioxidant-in-patients-with-acute-liver-diseases
#13
RANDOMIZED CONTROLLED TRIAL
Bertrand Nalpas, Philippe Ichaï, Laure Jamot, Nicolas Carbonell, Marika Rudler, Philippe Mathurin, François Durand, Guido Gerken, Michael Manns, Christian Trautwein, Dominique Larrey, Sylvie Radenne, Christophe Duvoux, Vincent Leroy, Jacques Bernuau, Jamila Faivre, Nicolas Moniaux, Christian Bréchot, Gilles Amouyal, Paul Amouyal, Didier Samuel
OBJECTIVE: No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH. DESIGN: double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72)...
2016: PloS One
https://www.readbyqxmd.com/read/26962875/a-perspective-on-implementing-a-quantitative-systems-pharmacology-platform-for-drug-discovery-and-the-advancement-of-personalized-medicine
#14
Andrew M Stern, Mark E Schurdak, Ivet Bahar, Jeremy M Berg, D Lansing Taylor
Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)-driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute...
July 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/26912003/double-blind-12-month-follow-up-placebo-controlled-trial-of-mifepristone-on-cognition-in-alcoholics-the-mifcog-trial-protocol
#15
RANDOMIZED CONTROLLED TRIAL
Kim Donoghue, Abigail Rose, Simon Coulton, Joanna Milward, Kylie Reed, Colin Drummond, Hilary Little
BACKGROUND: Increased levels of cortisol during acute alcohol withdrawal have been linked to cognitive deficits and depression. Preclinical research found that the glucocorticoid Type II receptor antagonist, mifepristone, prevented some of the neurotoxic effects of withdrawal and memory loss. Clinical trials have shown mifepristone effective in the treatment of depression. This study aims to examine the extent to which the glucocorticoid Type II receptor antagonist, mifepristone, when given to alcohol dependent males during the acute phase of alcohol withdrawal, will protect against the subsequent memory loss and depressive symptoms during abstinence from alcohol...
2016: BMC Psychiatry
https://www.readbyqxmd.com/read/26697847/effect-of-augmenting-cholinergic-function-on-gait-and-balance
#16
RANDOMIZED CONTROLLED TRIAL
Martina Mancini, Brett W Fling, Anne Gendreau, Jodi Lapidus, Fay B Horak, Kathy Chung, John G Nutt
BACKGROUND: Impaired mobility and falls are clinically important complications of Parkinson's disease (PD) and a major detractor from quality of life for which there are limited therapies. Pathological, neuroimaging and clinical evidence suggest that degeneration of cholinergic systems may contribute to impairments of balance and gait in PD. The proposed trial will examine the effects of augmentation of the cholinergic system on balance and gait. DESIGN: The study is a single-site, proof of concept, randomized, double-blind, cross-over trial in patients with PD...
2015: BMC Neurology
https://www.readbyqxmd.com/read/26579130/correlation-of-hsp70-serum-levels-with-gross-tumor-volume-and-composition-of-lymphocyte-subpopulations-in-patients-with-squamous-cell-and-adeno-non-small-cell-lung-cancer
#17
Sophie Gunther, Christian Ostheimer, Stefan Stangl, Hanno M Specht, Petra Mozes, Moritz Jesinghaus, Dirk Vordermark, Stephanie E Combs, Friedhelm Peltz, Max P Jung, Gabriele Multhoff
Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells...
2015: Frontiers in Immunology
https://www.readbyqxmd.com/read/26498386/roflumilast-for-asthma-efficacy-findings-in-placebo-controlled-studies
#18
RANDOMIZED CONTROLLED TRIAL
E O Meltzer, P Chervinsky, W Busse, K Ohta, P Bardin, D Bredenbröker, E D Bateman
BACKGROUND: The role of roflumilast as a potential asthma treatment is not yet fully understood. A series of placebo-controlled trials were undertaken in order to investigate the safety and efficacy of roflumilast in asthma. AIM: To evaluate the efficacy of roflumilast in nine randomized proof-of-concept, placebo-controlled monotherapy and combination therapy phase II and III clinical studies performed between 1997 and 2005. METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 24 weeks...
December 2015: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/26475445/development-of-the-sanofi-pasteur-tetravalent-dengue-vaccine-one-more-step-forward
#19
REVIEW
Bruno Guy, Olivier Briand, Jean Lang, Melanie Saville, Nicholas Jackson
Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals...
December 10, 2015: Vaccine
https://www.readbyqxmd.com/read/26027612/rationale-and-design-of-the-cyclosporine-to-improve-clinical-outcome-in-st-elevation-myocardial-infarction-patients-the-circus-trial
#20
RANDOMIZED CONTROLLED TRIAL
Nathan Mewton, Thien T Cung, Olivier Morel, Guillaume Cayla, Eric Bonnefoy-Cudraz, Gilles Rioufol, Denis Angoulvant, Patrice Guerin, Meyer Elbaz, Nicolas Delarche, Pierre Coste, Gerald Vanzetto, Marc Metge, Jean-François Aupetit, Bernard Jouve, Pascal Motreff, Christophe Tron, Jean-Noël Labeque, Pierre G Steg, Yves Cottin, Grégoire Range, Jerome Clerc, Patrick Coussement, Fabrice Prunier, Frederique Moulin, Olivier Roth, Loic Belle, Phillipe Dubois, Paul Barragan, Martine Gilard, Christophe Piot, Patrice Colin, Marie-Claude Morice, Jean-Pierre Monassier, Omar Ider, Jean Luc P Dubois-Randé, Thierry Unterseeh, Hervé Lebreton, Thierry Beard, Didier Blanchard, Gilles Grollier, Vincent Malquarti, Patrick Staat, Arnaud Sudre, Magnus J Hansson, Eskil Elmer, Inesse Boussaha, Claire Jossan, Anna Torner, Marc Claeys, David Garcia-Dorado, Michel Ovize
BACKGROUND: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. METHODS: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial...
June 2015: American Heart Journal
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