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Proof of concept Phase I or Phase II clinic trial

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https://www.readbyqxmd.com/read/28798986/a-phase-ii-multicentre-open-label-proof-of-concept-study-of-tasquinimod-in-hepatocellular-ovarian-renal-cell-and-gastric-cancers
#1
Bernard Escudier, Sandrine Faivre, Eric Van Cutsem, Nathalie Germann, Jean-Christophe Pouget, Ruth Plummer, Ignace Vergote, Fiona Thistlethwaite, Georg A Bjarnason, Robert Jones, Helen Mackay, Julien Edeline, Laetitia Fartoux, Hal Hirte, Amit Oza
BACKGROUND: Tasquinimod is a small molecule with immunomodulatory, anti-angiogenic, and anti-metastatic properties that targets the tumor microenvironment. This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors. PATIENTS AND METHODS: This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38), and gastric (n = 21) cancers...
August 10, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28767654/cancer-stem-cell-related-gene-expression-as-a-potential-biomarker-of-response-for-first-in-class-imipridone-onc201-in-solid-tumors
#2
Varun V Prabhu, Amriti R Lulla, Neel S Madhukar, Marie D Ralff, Dan Zhao, Christina Leah B Kline, A Pieter J Van den Heuvel, Avital Lev, Mathew J Garnett, Ultan McDermott, Cyril H Benes, Tracy T Batchelor, Andrew S Chi, Olivier Elemento, Joshua E Allen, Wafik S El-Deiry
Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction...
2017: PloS One
https://www.readbyqxmd.com/read/28760486/a-novel-brain-computer-interface-for-classification-of-social-joint-attention-in-autism-and-comparison-of-3-experimental-setups-a-feasibility-study
#3
Carlos P Amaral, Marco A Simões, Susana Mouga, João Andrade, Miguel Castelo-Branco
BACKGROUND: We present a novel virtual-reality P300-based Brain Computer Interface (BCI) paradigm using social cues to direct the focus of attention. We combined interactive immersive virtual-reality (VR) technology with the properties of P300 signals in a training tool which can be used in social attention disorders such as autism spectrum disorder (ASD). NEW METHOD: We tested the novel social attention training paradigm (P300-based BCI paradigm for rehabilitation of joint-attention skills) in 13 healthy participants, in 3 EEG systems...
July 29, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28738857/investigating-interventions-to-increase-uptake-of-hiv-testing-and-linkage-into-care-or-prevention-for-male-partners-of-pregnant-women-in-antenatal-clinics-in-blantyre-malawi-study-protocol-for-a-cluster-randomised-trial
#4
Augustine T Choko, Katherine Fielding, Nigel Stallard, Hendramoorthy Maheswaran, Aurelia Lepine, Nicola Desmond, Moses K Kumwenda, Elizabeth L Corbett
BACKGROUND: Despite large-scale efforts to diagnose people living with HIV, 54% remain undiagnosed in sub-Saharan Africa. The gap in knowledge of HIV status and uptake of follow-on services remains wide with much lower rates of HIV testing among men compared to women. Here, we design a study to investigate the effect on uptake of HIV testing and linkage into care or prevention of partner-delivered HIV self-testing alone or with an additional intervention among male partners of pregnant women...
July 24, 2017: Trials
https://www.readbyqxmd.com/read/28738565/zwitterionic-hydrophilic-interaction-liquid-chromatography-tandem-mass-spectrometry-with-hybridspe-precipitation-for-the-determination-of-intact-cisplatin-in-human-plasma
#5
Feifan Xie, Pieter Colin, Jan Van Bocxlaer
Cisplatin is a first-line chemotherapeutic for the treatment of a wide variety of cancers since its discovery in the 1960s. Although various techniques have been reported for the measurement of total platinum in biological matrices, such as inductively coupled plasma-mass spectrometry and derivatization procedures, a specific, sensitive and robust assay for the quantification of intact cisplatin is still lacking. Therefore, we present a rapid, selective, sensitive, and reliable UHPLC-MS/MS based method for the determination of intact cisplatin in human plasma in support of a Phase II clinical trial...
November 1, 2017: Talanta
https://www.readbyqxmd.com/read/28582570/phase-ii-proof-of-concept-trial-of-the-orexin-receptor-antagonist-filorexant-mk-6096-in-patients-with-major-depressive-disorder
#6
Kathryn M Connor, Paulette Ceesay, Jill Hutzlemann, Duane Snavely, Andrew D Krystal, Madhukar H Trivedi, Michael Thase, Christopher Lines, W Joseph Herring, David Michelson
Background: We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder (MDD). Methods: Six-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with MDD (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10mg or matching placebo. Results: Due to enrollment challenges the study was terminated early, resulting in insufficient statistical power to detect a pre-specified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment...
June 3, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28450365/critical-issues-for-the-translation-of-cardioprotection
#7
REVIEW
Gerd Heusch
The translation from numerous successful animal experiments on cardioprotection beyond that by reperfusion to clinical practice has to date been disappointing. Animal experiments often use reductionist approaches and are mostly performed in young and healthy animals which lack the risk factors, comorbidities, and comedications which are characteristics of patients suffering an acute myocardial infarction or undergoing cardiovascular surgery. Conceptually, it is still unclear by how much the time window for successful reperfusion is extended by preconditioning, and how long the duration of ischemia can be so that adjunct cardioprotection by postconditioning at reperfusion still protects...
April 28, 2017: Circulation Research
https://www.readbyqxmd.com/read/28372596/a-proof-of-concept-investigation-into-ketamine-as-a-pharmacological-treatment-for-alcohol-dependence-study-protocol-for-a-randomised-controlled-trial
#8
Amy McAndrew, Will Lawn, Tobias Stevens, Lilla Porffy, Brigitta Brandner, Celia J A Morgan
BACKGROUND: Worldwide, alcohol abuse is a burgeoning problem. Abstinence is key to allow recovery of physical and mental health as well as quality of life, but treatment for alcohol dependence is associated with high relapse rates. Preliminary data have suggested that a combined repeated ketamine and psychological therapy programme may be effective in reducing relapse in severe alcohol use disorder. This non-commercial proof-of-concept trial is aimed at making a preliminary assessment of the effectiveness of this combined treatment in this patient group...
April 4, 2017: Trials
https://www.readbyqxmd.com/read/28318420/bayesian-penalized-log-likelihood-ratio-approach-for-dose-response-clinical-trial-studies
#9
Yuanyuan Tang, Chunyan Cai, Liangrui Sun, Jianghua He
In literature, there are a few unified approaches to test proof of concept and estimate a target dose, including the multiple comparison procedure using modeling approach, and the permutation approach proposed by Klingenberg. We discuss and compare the operating characteristics of these unified approaches and further develop an alternative approach in a Bayesian framework based on the posterior distribution of a penalized log-likelihood ratio test statistic. Our Bayesian approach is much more flexible to handle linear or nonlinear dose-response relationships and is more efficient than the permutation approach...
February 13, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28174390/-surgical-regeneration-therapy-using-myoblast-sheets-for-severe-heart-failure
#10
Yoshiki Sawa
Heart failure is a life-threatening disorder worldwide, and the current end-stage therapies for severe heart failure are replacement therapies such as ventricular-assist devices and heart transplantation. Although these therapies have been reported to be useful, there are many issues in terms of the durability, complications, limited donors, adverse effect of continuous administration of immunosuppressive agents, and high costs involved. Recently, regenerative therapy based on genetic, cellular, or tissue engineering techniques has gained attention as a new therapy to overcome the challenges encountered in transplantation medicine...
January 2017: Kyobu Geka. the Japanese Journal of Thoracic Surgery
https://www.readbyqxmd.com/read/28153778/accelerating-the-clinical-development-of-protein-based-vaccines-for-malaria-by-efficient-purification-using-a-four-amino-acid-c-terminal-c-tag
#11
Jing Jin, Kathryn A Hjerrild, Sarah E Silk, Rebecca E Brown, Geneviève M Labbé, Jennifer M Marshall, Katherine E Wright, Sandra Bezemer, Stine B Clemmensen, Sumi Biswas, Yuanyuan Li, Aadil El-Turabi, Alexander D Douglas, Pim Hermans, Frank J Detmers, Willem A de Jongh, Matthew K Higgins, Rebecca Ashfield, Simon J Draper
Development of bespoke biomanufacturing processes remains a critical bottleneck for translational studies, in particular when modest quantities of a novel product are required for proof-of-concept Phase I/II clinical trials. In these instances the ability to develop a biomanufacturing process quickly and relatively cheaply, without risk to product quality or safety, provides a great advantage by allowing new antigens or concepts in immunogen design to more rapidly enter human testing. These challenges with production and purification are particularly apparent when developing recombinant protein-based vaccines for difficult parasitic diseases, with Plasmodium falciparum malaria being a prime example...
June 2017: International Journal for Parasitology
https://www.readbyqxmd.com/read/27980779/distinct-immunological-activation-profiles-of-dslim%C3%A2-and-promune%C3%A2-depend-on-their-different-structural-context
#12
Kerstin Kapp, Jacqueline Schneider, Lisa Schneider, Nadine Gollinge, Stefanie Jänsch, Matthias Schroff, Burghardt Wittig, Christiane Kleuss
INTRODUCTION: DNA-based TLR9 agonists are potent activators of the immune system. ProMune® and dSLIM® belong to different families of TLR9 agonists and both have been established as cancer immunotherapeutics in clinical proof-of-concept studies. Unfortunately, ProMune® failed in pivotal oncological trials. dSLIM®, the active ingredient of Lefitolimod (MGN1703), successfully finished a double-blinded, placebo-controlled phase II study in patients with advanced colorectal cancer, exhibiting improved progression-free survival and durable disease control...
December 2016: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/27941394/virological-efficacy-of-24-week-fozivudine-based-regimen-in-art-naive-patients-from-tanzania-and-c%C3%A3-te-d-ivoire
#13
Arne Kroidl, Frederic Ello, Jimson Mgaya, Tessa Lennemann, Raoul Moh, Lucas Maganga, Serge Eholie, Alain Pruvost, Elmar Saathoff, Pierre-Marie Girard, Ralph Zuhse, Friedrich von Massow, Xavier Anglaret, Michael Hoelscher, Christine Danel
OBJECTIVE: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing. DESIGN: Randomized clinical trial. METHODS: We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o...
February 20, 2017: AIDS
https://www.readbyqxmd.com/read/27883925/factors-associated-with-failure-of-oncology-drugs-in-late-stage-clinical-development-a-systematic-review
#14
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...
January 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27663483/pharmacodynamic-endpoints-as-clinical-trial-objectives-to-answer-important-questions-in-oncology-drug-development
#15
REVIEW
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
#16
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...
September 5, 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
#17
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
#18
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
#19
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
#20
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
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