scholarly journals Early-Phase Interventional Trials in Oral Cancer Prevention

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3845
Author(s):  
Caroline McCarthy ◽  
Stefano Fedele ◽  
Christian Ottensmeier ◽  
Richard J. Shaw
Keyword(s):  
Oral Cancer ◽  
Cancer Prevention ◽  
Early Phase ◽  
Drug Repurposing ◽  
Cancer Chemoprevention ◽  
Composite Endpoint ◽  
Phase Iii ◽  
Current Evidence ◽  
Clinical Endpoints ◽  
Early Phase Trials

The increasing breadth of molecular targets, promise of immune-targeted therapies and repurposed agents have heightened interest in cancer prevention. While, to date, testing of oral cancer chemoprevention strategies has failed to deliver therapeutic agents for routine clinical practice, there remains an urgent need for further clinical research to overcome this hurdle. Patients at the greatest risk of disease stand to benefit the most from inclusion in clinical trials; therefore, there is a need to carefully define this population using validated clinical and molecular markers. Safety, tolerability and the efficacy of interventions is assessed through carefully selected endpoints. These endpoints may include pharmacodynamic, clinical, histological and on-target molecular modifications as an individual or as a composite endpoint. Early-phase trials provide an area of opportunity to explore novel and repurposed agents in the setting of oral cancer chemoprevention, eventually leading to phase III trials with clinical endpoints such as transformation and clinical outcome; these studies are large, lengthy and expensive and should be reserved for the most promising of agents. This paper will explore current evidence in oral cancer chemoprevention, drug repurposing, selection of appropriate endpoints for early-phase trials and novel therapeutic angles in oral cancer chemoprevention.

scholarly journals A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

2007 ◽  
Vol 89 (3) ◽  
pp. 207-211 ◽  
Author(s):  
JF Thorpe ◽  
S Jain ◽  
TH Marczylo ◽  
AJ Gescher ◽  
WP Steward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Age Of Onset ◽  
Cancer Chemoprevention ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Prostate Cancer Prevention ◽  
Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

scholarly journals Experiences of establishing an academic early phase clinical trials unit

2017 ◽  
Vol 14 (4) ◽  
pp. 349-356 ◽  
Author(s):  
Sarah R Brown ◽  
Debbie Sherratt ◽  
Gill Booth ◽  
Julia Brown ◽  
Fiona Collinson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Late Phase ◽  
Knowledge Retention ◽  
Lessons Learned ◽  
Phase Iii ◽  
Trial Management ◽  
Early Phase Trials ◽  
Early Phase Trial ◽  
Phase Trial

Background: Early phase trials are essential in drug development, determining appropriate dose levels and assessing preliminary activity. These trials are undertaken by industry and academia, with increasing collaborations between the two. There is pressure to perform these trials quickly, safely, and robustly. However, there are inherent differences between developing and managing early phase, compared to late phase, drug trials. This article describes an approach to establishing an academically led early phase trial portfolio, highlighting lessons learned and sharing experiences. Methods: In 2009, the University of Leeds Clinical Trials Research Unit became the Clinical Trials Coordinating Office for Myeloma UK’s phase I and II trials. We embarked on a transition from working extensively in phase III to early phase trials development and conduct. This involved evaluating and revising our well-established standard operating procedures, visiting other academic early phase units, and developing essential new documentation and processes. Results: A core team of trial and data managers and statisticians was established to facilitate expertise and knowledge retention. A detailed training plan was implemented focussing on essential standard practices for early phase. These included pharmacovigilance, recruitment, trial design and set-up, data and site monitoring, and oversight committees. Training in statistical methods for early phase trials was incorporated. Conclusion: Initial scoping of early phase trial management and conduct was essential in establishing this early phase portfolio. Many of the processes developed were successful. However, regular review and evaluation were implemented to enable changes and ensure efficiencies. It is recommended that others embarking on this venture build on the experiences described in this article.

scholarly journals Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Nalinie Joharatnam-Hogan ◽  
Leo Alexandre ◽  
James Yarmolinsky ◽  
Blossom Lake ◽  
Nigel Capps ◽  
...  
Keyword(s):  
Drug Development ◽  
Controlled Trial ◽  
Randomised Trial ◽  
Drug Repurposing ◽  
Cancer Chemoprevention ◽  
Cost Effective ◽  
Evidence Base ◽  
Phase Iii ◽  
Epidemiological Research ◽  
Repurposed Drugs

Abstract Purpose of Review Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. Recent Findings In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with “target” trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. Summary We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.

scholarly journals Level of Evidence for FDA Drug Approvals in Pivotal Clinical Trials of Hematological Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Samer Al Hadidi ◽  
Carlos A. Ramos
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Hematological Malignancies ◽  
Phase Iii ◽  
Clinical Activity ◽  
Level Of Evidence ◽  
Phase Iii Clinical Trials ◽  
Early Phase Trials ◽  
Phase Iii Trials ◽  
Drug Approvals

BACKGROUND Clinical trials are integral to improve treatment outcomes for patients with hematological malignancies. Although early phase (I/II) clinical trials may provide evidence of clinical efficacy, the main goal for early phase trials is to assess safety signal. Results of phase III clinical trials provide the strongest evidence to support the use of new cancer medications. The Food and Drug Administration (FDA) is responsible to ensure appropriate control and supervision of pharmaceutical drugs. METHODS On the basis of publicly available study protocols and FDA reviews, the authors reviewed the level of evidence in 52 clinical trials supporting 49 drug approvals from 2016 to 2020. Data cut point was May 2020. These trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and multiple myeloma. RESULTS A total of 52 clinical trials were assessed in the 5 years period. Phase III trials supported 61.5% while earlier phase trials supported 36.5% of subsequent FDA hematological malignancies approvals. The level of evidence to support FDA approvals improved with time with 50% of approvals in 2016 and 2017 supported by phase III clinical trials compared to 69% in 2019. Approvals were based on early phase trials in mantle cell lymphoma (100%), chronic myeloid leukemia (100%), diffuse large B cell lymphoma (100%), classic Hodgkin's lymphoma (67%) and acute myeloid leukemia (56%). Phase III trials enrolled 87% of the patients (14238 from16429 patients). Eighteen drug approvals (37% of all approvals) were based on 13% of the total number of patients in the studied period. CONCLUSIONS Level of evidence to support drug approvals in hematological malignancies was based on early phase trials in more than a third of the times. Although early phase studies are appropriate for safety signals, further clinical activity assessment should be done to support the use of new drugs to treat hematological malignancies. Previous successful early phase studies failed to show clinical activity in phase III studies. Despite the fact that use of new approved drugs based on early phase studies evidence may be needed, patients and healthcare providers should be aware of such possibility when using newly approved medications. Figure Disclosures Ramos: Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding.

Cancer prevention

2018 ◽  
Author(s):  
Jim Cassidy ◽  
Donald Bissett ◽  
Roy A. J. Spence OBE ◽  
Miranda Payne ◽  
Gareth Morris-Stiff
Keyword(s):  
Quality Of Life ◽  
Clinical Trials ◽  
Cancer Therapy ◽  
Cancer Prevention ◽  
Early Phase ◽  
Early Phase Trials ◽  
Phases Of Development ◽  
Trail Design

Introduces the reader to importance of clinical trials in cancer therapy. Describes the phases of development and some of the “traditional” guidelines for such studies. Focuses particularly on early phase trials of novel compounds. Also describes endpoints used in such trials. Section on quality of life which highlights the growing importance of this aspect of trail design and interpretation

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

scholarly journals Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds?

2021 ◽  
Vol 22 (15) ◽  
pp. 8223
Author(s):  
Violetta Krajka-Kuźniak ◽  
Wanda Baer-Dubowska
Keyword(s):  
Cancer Prevention ◽  
Signaling Pathways ◽  
Current Knowledge ◽  
Cancer Chemoprevention ◽  
Antioxidant Response ◽  
Natural Food ◽  
Related Factor ◽  
Nuclear Factor ◽  
Edible Plant ◽  
Prevention And Therapy

Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-κB (nuclear factor–kappa B) signaling pathways play a central role in suppressing or inducing inflammation and angiogenesis processes. Therefore, they are involved in many steps of carcinogenesis through cooperation with multiple signaling molecules and pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention and therapy. Several hundreds of phytochemicals, mainly edible plant and vegetable components, were shown to activate Nrf2 and mediate antioxidant response. A similar number of phytochemicals was revealed to affect NF-κB. While activation of Nrf2 and inhibition of NF-κB may protect normal cells against cancer initiation and promotion, enhanced expression and activation in cancer cells may lead to resistance to conventional chemo- or radiotherapy. Most phytochemicals, through different mechanisms, activate Nrf2, but others, such as luteolin, can act as inhibitors of both Nrf2 and NF-κB. Despite many experimental data confirming the above mechanisms currently, limited evidence exists demonstrating such activity in humans. Combinations of phytochemicals resembling that in a natural food matrix but allowing higher concentrations may improve their modulating effect on Nrf2 and NF-κB and ultimately cancer prevention and therapy. This review presents the current knowledge on the effect of selected phytochemicals and their combinations on Nrf2 and NF-κB activities in the above context.

scholarly journals Nutrition in Menopausal Women: A Narrative Review

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2149
Author(s):  
Thais R. Silva ◽  
Karen Oppermann ◽  
Fernando M. Reis ◽  
Poli Mara Spritzer
Keyword(s):  
Body Composition ◽  
Postmenopausal Women ◽  
Bone Fractures ◽  
Blood Pressure Reduction ◽  
Antioxidant Properties ◽  
Narrative Review ◽  
Current Evidence ◽  
Beneficial Effects ◽  
Clinical Endpoints ◽  
Postmenopausal Period

Among the various aspects of health promotion and lifestyle adaptation to the postmenopausal period, nutritional habits are essential because they concern all women, can be modified, and impact both longevity and quality of life. In this narrative review, we discuss the current evidence on the association between dietary patterns and clinical endpoints in postmenopausal women, such as body composition, bone mass, and risk markers for cardiovascular disease. Current evidence suggests that low-fat, plant-based diets are associated with beneficial effects on body composition, but further studies are needed to confirm these results in postmenopausal women. The Mediterranean diet pattern along with other healthy habits may help the primary prevention of bone, metabolic, and cardiovascular diseases in the postmenopausal period. It consists on the use of healthy foods that have anti-inflammatory and antioxidant properties, and is associated with a small but significant decrease in blood pressure, reduction of fat mass, and improvement in cholesterol levels. These effects remain to be evaluated over a longer period of time, with the assessment of hard outcomes such as bone fractures, diabetes, and coronary ischemia.

BOIN: A novel Bayesian design platform to accelerate early phase brain tumor clinical trials

2021 ◽  
Author(s):  
Ying Yuan ◽  
Jing Wu ◽  
Mark R Gilbert
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Early Phase ◽  
Late Onset ◽  
Single Agent ◽  
Phase Iii ◽  
Combination Regimen ◽  
Operating Characteristics ◽  
Optimal Interval ◽  
Phase Iii Trials

Abstract Despite decades of extensive research, the progress in developing effective treatments for primary brain tumors lags behind that of other cancers, largely due to the unique challenges of brain tumors (e.g., the blood-brain barrier and high heterogeneity) that limit the delivery and efficacy of many therapeutic agents. One way to address this issue is to employ novel trial designs to better optimize the treatment regimen (e.g., dose and schedule) in early phase trials to improve the success rate of subsequent phase III trials. The objective of this article is to introduce Bayesian optimal interval (BOIN) designs as a novel platform to design various types of early phase brain tumor trials, including single-agent and combination regimen trials, trials with late-onset toxicities, and trials aiming to find the optimal biological dose (OBD) based on both toxicity and efficacy. Unlike many novel Bayesian adaptive designs, which are difficult to understand and complicated to implement by clinical investigators, the BOIN designs are self-explanatory and user friendly, yet yield more robust and powerful operating characteristics than conventional designs. We illustrate the BOIN designs using a phase I clinical trial of brain tumor, and provide software (freely available at www.trialdesign.org) to facilitate the application of the BOIN design.

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