scholarly journals Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Jiali Du ◽  
Jichun Gu ◽  
Ji Li
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Solid Tumours ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Phase Iii Trials ◽  
Exploitation And Exploration ◽  
Different Levels

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

Clinical trial risk reduction in non-small cell lung cancer though the use of biomarkers and receptor-targeted therapies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8040-8040
Author(s):  
Adam Falconi ◽  
Gilberto Lopes ◽  
Jayson L. Parker
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Success Rate ◽  
Targeted Therapies ◽  
Phase Iii ◽  
Clinical Testing ◽  
Phase Ii Trials ◽  
Phase Iii Trials

8040 Background: We analyzed the risk of clinical trial failure duringnon-small cell lung cancer (NSCLC) drug development between 1998 and 2012. Methods: NSCLC drug development was investigated using trial disclosures from publically available resources. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use treatment relevant endpoints. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD). Results: 2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than the expected industry aggregate rates (16.5%). The success of phase III trials was found to be the biggest obstacle for drug approval with a success rate of only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development was calculated to be 1.89 billion US dollars. Use of biomarkers decreased drug development cost by 26% to 1.4 billion US dollars. Potential savings may be even higher if fewer clinical trials are required for successful development. Conclusions: Physicians that enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.

Assessing the risk of serious adverse events (SAEs) and death in non-small cell lung cancer (NSCLC) trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21576-e21576
Author(s):  
Nirali Marvania ◽  
Abigail Sy Chan ◽  
Joseph Abraham ◽  
Kenneth David Miller
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Phase I ◽  
Fixed Effects ◽  
Advanced Nsclc ◽  
Critical Role ◽  
Morbidity And Mortality ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
Nsclc Patients

e21576 Background: Lung cancer is a leading cause of morbidity and mortality despite advances in targeted therapy and immunotherapy. Clinical trials play a critical role in improving treatment options however, pose significant known and unknown risks. The purpose of this study was to analyze the risk of SAEs (Grade 3 and 4 toxicity) and deaths in advanced NSCLC patients participating in phase I/II and III clinical trials. Methods: A literature search using Clinicaltrials.gov was conducted to identify published phase I/II and III clinical trials in advanced NSCLC patients. The data extracted included study name, total number of participants, SAEs, and deaths attributable to a study drug. A fixed-effects model was implemented to estimate summary proportions of SAEs among participants. The Freeman-Tukey double arcsine transformation was applied to stabilize the variances of SAEs and mortality proportions. Results: We evaluated 112 studies, of which 87% were phase I/II, and 13% were phase III clinical trials. Study sample sizes ranged from 7 to 659 patients for phase I/II studies and from 186 to 1391 for phase III studies. 107 studies had SAEs while 5 phase I/II studies had no SAEs reported. The overall estimated percentage of SAEs was 39.5% (95% Confidence Interval, CI: 38.8%, 40.2%). The estimated percentages of patients with SAE in phase I/II and phase III trials were 40.9% (95%CI: 39.8%, 42.0%) and 38.7% (95%CI: 37.8%, 39.6%), respectively (p = 0.001). The estimated percentages of deaths among patients were 1.1% (95%CI: 0.90%, 1.3%) overall, 1.1% (95%CI: 0.7%, 1.5%) in phase I/II trials and 1.7% (95%CI: 1.5%, 2.0%) in phase III trials. The difference in mortality between phase I/II and phase III trials was not statistically significant (p = 0.408). Conclusions: Patients with advanced stages (III/IV) of NSCLC have a high risk of morbidity and mortality from their primary disease and also from their treatment. Our study demonstrated SAEs and toxic deaths attributable to the treatment of approximately 40% and 1%, respectively. Phase I/II trials patients are at a slightly higher risk of SAEs compared to patients participating in phase III trials, although the differences might not be clinically significant.

scholarly journals Strategic inclusion of regions in multiregional clinical trials

2018 ◽  
Vol 16 (1) ◽  
pp. 98-105
Author(s):  
Seung Yeon Song ◽  
Deborah Chee ◽  
EunYoung Kim
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Phase Iii ◽  
Local Study ◽  
International Conference ◽  
Trial Conduct ◽  
Increasing Trend ◽  
Phase Iii Trials

Background With the recent publication of the International Conference on Harmonisation E17 guideline and major reforms in China underway, the platform for clinical trial conduct is expected to change. This study aims to assess the strategic inclusion of regions in clinical trials and its change in trends over the past decade. Methods The ClinicalTrials.gov registry was searched for clinical trials registered by the top 10 pharmaceutical companies between 1 January 2008 and 31 December 2017. Extracted data included phase, disease type, intervention, study start year, and region. Trial type was classified as either a local study or a multiregional clinical trial as per the International Conference on Harmonisation E17 guideline. Results Of 2488 phase I, 1855 phase II, and 1999 phase III trials included, the majority of phase I trials were local studies (76.8%), while the majority of phase II (66.0%) and phase III (72.2%) trials were multiregional clinical trials. The proportion of multiregional clinical trials showed an increasing trend for all phases ( p < 0.01). Although North America and Europe remained the main locations, increasing trends of inclusion of other regions, such as East Asia, were noted. Conclusion Globalization of drug development is evident with the increasing trend of multiregional clinical trial. Regulatory authorities as well as the pharmaceutical industry should prepare for the evolving setting of clinical research and problems that can arise from these changes.

scholarly journals Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 14 (3) ◽  
pp. 280
Author(s):  
Rita Rebelo ◽  
Bárbara Polónia ◽  
Lúcio Lara Santos ◽  
M. Helena Vasconcelos ◽  
Cristina P. R. Xavier
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pancreatic Ductal Adenocarcinoma ◽  
De Novo ◽  
Drug Repurposing ◽  
Metastatic Tumor ◽  
Therapeutic Options ◽  
Ductal Adenocarcinoma ◽  
Clinical Indication ◽  
Novel Treatments

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

scholarly journals Increased Expression of Tissue Transglutaminase in Pancreatic Ductal Adenocarcinoma and Its Implications in Drug Resistance and Metastasis

2006 ◽  
Vol 66 (21) ◽  
pp. 10525-10533 ◽  
Author(s):  
Amit Verma ◽  
Huamin Wang ◽  
Bramanandam Manavathi ◽  
Jansina Y. Fok ◽  
Aman P. Mann ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Tissue Transglutaminase ◽  
Ductal Adenocarcinoma

scholarly journals NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice

BMC Cancer ◽  
2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Ferdinando De Vita ◽  
Jole Ventriglia ◽  
Antonio Febbraro ◽  
Maria Maddalena Laterza ◽  
Alessio Fabozzi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Sign in / Sign up

Export Citation Format

Share Document