Metal-Protein Attenuating Compounds in Neurodegenerative Diseases

2016 ◽  
Author(s):  
Peng Lei ◽  
Scott Ayton ◽  
Ashley I. Bush
Keyword(s):  
Neurodegenerative Diseases ◽  
Drug Targets ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Alternative Drug ◽  
Phase Iii Trials ◽  
Specific Proteins ◽  
Copper Zinc ◽  
Lateral Sclerosis ◽  
Disease Specific

Neurodegenerative disorders including Alzheimer’s (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are progressive diseases of the aging population with currently few therapeutic options. While aggregation and deposition of disease-specific proteins link the pathologies of these diseases, targeting these aggregating proteins with therapeutics has not yet been successful in clinical trial. This chapter profiles metals (copper, zinc, and iron) as alternative drug targets for neurodegeneration. Complex changes to metals occur in these neurodegenerative diseases. Accumulating evidences have demonstrated that perturbations to metal homeostasis contribute to the progression of neuronal dysfunction and death. Importantly, several phase II trials have shown that correcting metal dyshomeostasis improves clinical outcomes; the chapter argues that it is now time to explore the therapeutic utility of metal-based drugs in larger, phase III trials.

Biofeedback

2016 ◽  
Vol 4 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Paul Lehrer
Keyword(s):  
Phase Ii ◽  
Real Life ◽  
Phase Iii ◽  
Controlled Trials ◽  
Clinical Environment ◽  
Phase Ii Trials ◽  
Research Support ◽  
Phase Iii Trials ◽  
Psychosomatic Problems ◽  
Biofeedback Research

Although evidence supports the efficacy of biofeedback for treating a number of disorders and for enhancing performance, significant barriers block both needed research and payer support for this method. Biofeedback has demonstrated effects in changing psychophysiological substrates of various emotional, physical, and psychosomatic problems, but payers are reluctant to reimburse for biofeedback services. A considerable amount of biofeedback research is in the form of relatively small well-controlled trials (Phase II trials). This article argues for greater payer support and research support for larger trials in the “real life” clinical environment (Phase III trials) and meta-analytic reviews.

scholarly journals Targeting Angiogenesis in Prostate Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2676 ◽  
Author(s):  
Zsombor Melegh ◽  
Sebastian Oltean
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Phase Iii ◽  
Refractory Disease ◽  
Phase Ii Trials ◽  
Angiogenic Activity ◽  
Angiogenic Therapy ◽  
Resistant Refractory ◽  
Castration Resistant ◽  
Phase Iii Trials

Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Although localized disease can be effectively treated with established surgical and radiopharmaceutical treatments options, the prognosis of castration-resistant advanced prostate cancer is still disappointing. The objective of this study was to review the role of angiogenesis in prostate cancer and to investigate the effectiveness of anti-angiogenic therapies. A literature search of clinical trials testing the efficacy of anti-angiogenic therapy in prostate cancer was performed using Pubmed. Surrogate markers of angiogenic activity (microvessel density and vascular endothelial growth factor A (VEGF-A) expression) were found to be associated with tumor grade, metastasis, and prognosis. Six randomizedstudies were included in this review: two phase II trials on localized and hormone-sensitive disease (n = 60 and 99 patients) and four phase III trials on castration-resistant refractory disease (n = 873 to 1224 patients). Although the phase II trials showed improved relapse-free survival and stabilisation of the disease, the phase III trials found increased toxicity and no significant improvement in overall survival. Although angiogenesis appears to have an important role in prostate cancer, the results of anti-angiogenic therapy in castration-resistant refractory disease have hitherto been disappointing. There are various possible explanations for this lack of efficacy in castration-resistant refractory disease: redundancy of angiogenic pathways, molecular heterogeneity of the disease, loss of tumor suppressor protein phosphatase and tensin homolog (PTEN) expression as well as various VEGF-A splicing isoforms with pro- and anti-angiogenic activity. A better understanding of the molecular mechanisms of angiogenesis may help to develop effective anti-angiogenic therapy in prostate cancer.

scholarly journals Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials

2020 ◽  
Vol 10 ◽  
Author(s):  
Pierre-Yves Cren ◽  
Loïc Lebellec ◽  
Thomas Ryckewaert ◽  
Nicolas Penel
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Multikinase Inhibitors ◽  
Randomized Phase Ii ◽  
Phase Iii Trials

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

Capecitabine and irinotecan (XELIRI) in first-line treatment of metastatic colorectal cancer (mCRC): A systematic review of controlled clinical trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
S. Sukumaran ◽  
N. Pavlakis ◽  
K. B. Pittman ◽  
K. Patterson ◽  
T. J. Price
Keyword(s):  
Phase Ii ◽  
Phase Iii ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
First Line ◽  
Hand Foot Syndrome ◽  
Phase Iii Trials ◽  
Grade 3 ◽  
Phase Ii And Iii ◽  
First Line Treatment

e15100 Background: Irinotecan and 5-Fluorouracil based combination is an effective regimen for mCRC. Capecitabine, an oral fluoropyrimidine, is a convenient alternative to intravenous 5- Fluorouracil. This study aims to systematically review all published and unpublished controlled phase II and III trials of XELIRI combination, used in first line treatment of mCRC, reported from 2000–2008, to describe its efficacy and safety. Methods: A literature search of MEDLINE, EMBASE, CINAHL and proceedings from ASCO, ESMO and WGIC was conducted. The primary end point was response rate (RR), secondary endpoints include: time to progression (TTP), overall survival (OS) and toxicity. Results: Thirty non-randomised phase II trials (n = 1380) along with 6 randomised phase II and 3 phase III trials, were included (pooled n = 1478). The daily dose of capecitabine ranged from 1,800 mg/m2 to 2,500 mg/m2 for 7 to 14 days per cycle and the dose of irinotecan varied from 180mg/m2 to 350 mg/m2, over a 3 week period per cycle. Amongst the non-randomised studies, the median patient age was 61 years (53–72).The median RR was 46.75% (25–78%). The median reported TTP was 7.9 months (mo) (5- 9.9 mo) and the median OS was 15.6 months (7–24.8 mo). Grade 3–4 toxicity incidence was: diarrhoea (21.5%), neutropenia (12%), vomiting (12.5%), fatigue (6%) and Hand-foot syndrome (6%). The pooled incidence of febrile neutropenia was 2.5%. Amongst the randomised trials, the comparator regimens were XELOX or FOLFIRI. Median age was 65 years (61–74). RR for XELIRI was 39% (34–56%) compared to 47% (27–61.8%) for the non XELIRI comparator arms. Median reported TTP was 8.2 mo (5.7–12.5 mo) for the XELIRI arms and 9.2 mo for the comparator arms. Conclusions: XELIRI is an effective and feasible regime in the first line management of mCRC. However the optimal role of this combination remains to be established. No significant financial relationships to disclose.

The prevalence of objectively measurable disease in phase III trials of metastatic castration-resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 215-215 ◽  
Author(s):  
Ankit Madan ◽  
Mary K Baker ◽  
Jori E May ◽  
Gurudatta Naik ◽  
Sejong Bae ◽  
...  
Keyword(s):  
Phase Ii ◽  
Bone Scan ◽  
Strong Association ◽  
Specific Antigen ◽  
Phase Iii ◽  
Disease Rate ◽  
Phase Ii Trials ◽  
Significant Difference ◽  
Measurable Disease ◽  
Phase Iii Trials

215 Background: Given the historical low prevalence of measurable disease in mCRPC, phase II trials have employed suboptimal endpoints accounting for prostate specific antigen (PSA) and bone scan changes. Changes in bone scan and PSA have not always translated to survival improvement. Improved computerized tomography technology may be increasing the proportion of men with measurable disease, suggesting that measurable changes need to be reconsidered. We analyzed phase III trials of mCRPC to systematically quantitate the proportion of mCRPC with measurable disease. Methods: Data from the both arms of published phase III trials of mCRPC were eligible for analysis. Baseline characteristics were required including the number enrolled, setting (pre-docetaxel [D], D-based, post-D), proportion of patients with measurable disease and the year of completion of trial accrual. General Linear Model was used to evaluate the difference in measurable disease rate based on setting and year of completion of accrual. Results: Seventeen phase III trials totaling 17,609 men with mCRPC were evaluable; 5160 were pre-D, 7573 were D-based and 4876 were post-D. The trials completed accrual between 2002 and 2012. Ten trials used RECIST 1.0, 5 trials used RECIST 1.1 and 2 trials used other criteria. The overall proportion of men with measurable disease was 47.8%. The measurable disease rate (range) in trials in the pre-D setting was 40.5% (30.5-57), in the D-based setting was 51.9% (29.1-87.5), and in the post-D setting was 48.9% (38.8-56.6). There was no statistical difference in the proportion of men with measurable disease based on setting or year of completion of accrual. Conclusions: The proportion of men with measurable disease in phase III trials of mCRPC completing accrual between 2002 and 2012 was 47.8%% with no significant difference based on setting or year of completing accrual. Given these higher measurable disease rates compared to historical rates and recent demonstration of strong association of RECIST changes with OS in mCRPC, RECIST changes need to be considered as a co-primary endpoint in phase II trials to obtain a firm signal of efficacy before launching phase III trials.

Point: Intraperitoneal Chemotherapy in the Management of Ovarian Cancer

2004 ◽  
Vol 2 (6) ◽  
pp. 549-554 ◽  
Author(s):  
Maurie Markman
Keyword(s):  
Ovarian Cancer ◽  
Small Volume ◽  
Advanced Ovarian Cancer ◽  
Phase Iii ◽  
Rational Approach ◽  
Pharmacokinetic Studies ◽  
Phase Ii Trials ◽  
Intraperitoneal Therapy ◽  
Phase Iii Trials ◽  
Optimal Approach

Both preclinical considerations and results of phase I safety and pharmacokinetic studies provided support for the argument that intraperitoneal antineoplastic drug delivery should be a rational approach to the management of ovarian cancer. Subsequently conducted phase II trials exploring regional treatment revealed surgically documented objective responses when the approach was employed as a second-line therapy. Recently, the results of three randomized phase III trials have shown that the use of primary cisplatin-based intraperitoneal therapy leads to superior survival compared with intravenous cisplatin-based treatment in patients with small-volume residual advanced ovarian cancer after initial surgical cytoreduction. Further exploration of this unique management strategy is indicated to develop an optimal approach that maintains the demonstrated enhanced efficacy while reducing the toxicity (principally because of cisplatin) of treatment.

Point/Counterpoint: Do We De-escalate Treatment of HPV-Associated Oropharynx Cancer Now? And How?

2019 ◽  
pp. 364-372 ◽  
Author(s):  
Lori J. Wirth ◽  
Barbara Burtness ◽  
Cherie-Ann O. Nathan ◽  
Vincent Grégoire ◽  
Jeremy Richmon
Keyword(s):  
First Generation ◽  
Dose Intensity ◽  
Multimodality Treatment ◽  
Phase Iii ◽  
Oropharyngeal Carcinoma ◽  
Phase Ii Trials ◽  
Primary Surgery ◽  
Phase Iii Trials ◽  
Major Trend ◽  
Cure Rates

HPV-positive (HPV+) oropharyngeal carcinoma (OPC) continues to increase in incidence across the globe. Multimodality treatment offers a high likelihood of cure in HPV+ OPC but comes at a high cost of treatment-related morbidity. As a result, de-escalation of treatment to limit toxicity without compromising high cure rates has emerged as a major trend in head and neck cancer clinical research. Primary surgery with minimally invasive resection of the primary disease may allow for the elimination of chemotherapy and decrease radiation dose intensity. Primary dose-reduced radiation, with or without systemic therapy, is also under study, as is replacing concurrent cisplatin with newer systemic agents. Numerous institutional series and phase II trials have been presented, and the first generation of de-escalation randomized phase III trials have now been published. The various combinatorial multimodality strategies to achieve less intensive and toxic therapy are many. Has the time come for de-escalation as a standard approach to HPV+ OPC? The pros and cons, as well as the best approaches for de-escalated treatment of HPV+ OPC, are debated here.

Where have we gone wrong? Phase II trials (Ph2t) do not inform the results of phase III trials (Ph3t) in platinum resistant ovarian cancer (PROC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5559-5559 ◽  
Author(s):  
Tami Grunewald ◽  
Monica Tang ◽  
Julia Chen ◽  
Sally Lord ◽  
Michael Friedlander ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Platinum Resistant ◽  
Phase Iii Trials
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