scholarly journals Anti-tumour drugs of marine origin currently at various stages of clinical trials (review)

2021 ◽  
Vol 12 (2) ◽  
pp. 265-280
Author(s):  
E. A. Bocharova ◽  
N. I. Kopytina ◽  
Е. Е. Slynko
Keyword(s):  
Clinical Trials ◽  
Metastatic Cancer ◽  
Modern Society ◽  
Brentuximab Vedotin ◽  
Marine Organisms ◽  
Eribulin Mesylate ◽  
Marine Origin ◽  
Number Of Patients ◽  
Cytotoxic Compounds ◽  
Oncological Diseases

Oncological diseases for a long time have remained one of the most significant health problems of modern society, which causes great losses in its labour and vital potential. Contemporary oncology still faces unsolved issues as insufficient efficacy of treatment of progressing and metastatic cancer, chemoresistance, and side-effects of the traditional therapy which lead to disabilities among or death of a high number of patients. Development of new anti-tumour preparations with a broad range of pharmaceutical properties and low toxicity is becoming increasingly relevant every year. The objective of the study was to provide a review of the recent data about anti-tumour preparations of marine origin currently being at various phases of clinical trials in order to present the biological value of marine organisms – producers of cytotoxic compounds, and the perspectives of their use in modern biomedical technologies. Unlike the synthetic oncological preparations, natural compounds are safer, have broader range of cytotoxic activity, can inhibit the processes of tumour development and metastasis, and at the same time have effects on several etiopathogenic links of carcinogenesis. Currently, practical oncology uses 12 anti-tumour preparations of marine origin (Fludarabine, Cytarabine, Midostaurin, Nelarabine, Eribulin mesylate, Brentuximab vedotin, Trabectedin, Plitidepsin, Enfortumab vedotin, Polatuzumab vedotin, Belantamab mafodotin, Lurbinectedin), 27 substances are at different stages of clinical trials. Contemporary approaches to the treatment of oncological diseases are based on targeted methods such as immune and genetic therapies, antibody-drug conjugates, nanoparticles of biopolymers, and metals. All those methods employ bioactive compounds of marine origin. Numerous literature data from recent years indicate heightened attention to the marine pharmacology and the high potential of marine organisms for the biomedicinal and pharmaceutic industries.

ANTIBODY-DRUG CONJUGATES FOR TARGETED CANCER THERAPY

2019 ◽  
Vol 65 (6) ◽  
pp. 777-784
Author(s):  
David Korman
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Gemtuzumab Ozogamicin ◽  
Brentuximab Vedotin ◽  
Cytostatic Agent ◽  
Cytostatic Agents ◽  
Drug Conjugates ◽  
Natural Substances ◽  
Intracellular Release ◽  
High Antitumor Activity

Monoclonal antibody (MAB) conjugates with cytostatic agents (ADC) are intended for selective delivery of a cytostatic agent to a tumor cell. Three ADC have been approved for clinical use (gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab-DM1); a few dozens of other ADC are undergoing clinical trials. Several derivatives of natural substances (antibiotics and inhibitors of microtubules) having a high antitumor activity are used as cytostatic agents included in ADC. They are inapplicable in clinical practice as self-sustained drugs due to their considerable toxicity. Of great importance for the implementation of the ADC effect is the character of a linker connecting MAB with a cytostatic agent and ensuring selective intracellular release after ADC internalization. The structure, mechanisms of action, and the results of clinical trials of a number of ADC are considered here as an illustration (by way of example). The development of ADC can help introduce new effective cytostatic agents into clinical practice.

scholarly journals Bayesian adaptive design of early-phase clinical trials for precision medicine based on cancer biomarkers

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shinjo Yada
Keyword(s):  
Neural Network ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Early Phase ◽  
Patient Specific ◽  
Specific Gene ◽  
Cancer Type ◽  
Background Characteristics ◽  
Number Of Patients ◽  
Early Phase Clinical Trials

Abstract Cancer tissue samples obtained via biopsy or surgery were examined for specific gene mutations by genetic testing to inform treatment. Precision medicine, which considers not only the cancer type and location, but also the genetic information, environment, and lifestyle of each patient, can be applied for disease prevention and treatment in individual patients. The number of patient-specific characteristics, including biomarkers, has been increasing with time; these characteristics are highly correlated with outcomes. The number of patients at the beginning of early-phase clinical trials is often limited. Moreover, it is challenging to estimate parameters of models that include baseline characteristics as covariates such as biomarkers. To overcome these issues and promote personalized medicine, we propose a dose-finding method that considers patient background characteristics, including biomarkers, using a model for phase I/II oncology trials. We built a Bayesian neural network with input variables of dose, biomarkers, and interactions between dose and biomarkers and output variables of efficacy outcomes for each patient. We trained the neural network to select the optimal dose based on all background characteristics of a patient. Simulation analysis showed that the probability of selecting the desirable dose was higher using the proposed method than that using the naïve method.

scholarly journals Reporting of harms in oncological clinical study reports submitted to the European Medicines Agency compared to trial registries and publications—a methodological review

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Asger S. Paludan-Müller ◽  
Perrine Créquit ◽  
Isabelle Boutron
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Study ◽  
Primary Source ◽  
European Medicines Agency ◽  
Clinical Trial Registries ◽  
Number Of Patients ◽  
Journal Publications ◽  
Clinical Study Reports ◽  
Completeness Of Reporting

Abstract Background An accurate and comprehensive assessment of harms is a fundamental part of an accurate weighing of benefits and harms of an intervention when making treatment decisions; however, harms are known to be underreported in journal publications. Therefore, we sought to compare the completeness of reporting of harm data, discrepancies in harm data reported, and the delay to access results of oncological clinical trials between three sources: clinical study reports (CSRs), clinical trial registries and journal publications. Methods We used the EMA clinical data website to identify all trials submitted to the EMA between 2015 and 2018. We retrieved all CSRs and included all phase II, II/III or III randomised controlled trials (RCTs) assessing targeted therapy and immunotherapy for cancer. We then identified related records in clinical trial registries and journals. We extracted harms data for eight pre-specified variables and determined the completeness of reporting of harm data in each of the three sources. Results We identified 42 RCTs evaluating 13 different drugs. Results were available on the EMA website in CSRs for 37 (88%) RCTs, ClinicalTrials.gov for 36 (86%), the European Clinical Trials Register (EUCTR) for 20 (48%) and in journal publications for 32 (76%). Harms reporting was more complete in CSRs than other sources. We identified marked discrepancies in harms data between sources, e.g. the number of patients discontinuing due to adverse events differed in CSRs and clinical trial registers for 88% of trials with data in both sources. For CSRs and publications, the corresponding number was 90%. The median (interquartile range) delay between the primary trial completion date and access to results was 4.34 (3.09–7.22) years for CSRs, 2.94 (1.16–4.52) years for ClinicalTrials.gov, 5.39 (4.18–7.33) years for EUCTR and 2.15 (0.64–5.04) years for publications. Conclusions Harms of recently approved oncological drugs were reported more frequently and in more detail in CSRs than in trial registries and journal publications. Systematic reviews seeking to address harms of oncological treatments should ideally use CSRs as the primary source of data; however, due to problems with access, this is currently not feasible.

scholarly journals Low-grade Serous Ovarian Carcinoma

2018 ◽  
Vol 78 (10) ◽  
pp. 972-976 ◽  
Author(s):  
Enzo Ricciardi ◽  
Thaïs Baert ◽  
Beyhan Ataseven ◽  
Florian Heitz ◽  
Sonia Prader ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Ovarian Carcinoma ◽  
Systemic Treatment ◽  
Hormonal Treatment ◽  
Current Treatment ◽  
Low Grade ◽  
Separate Entity ◽  
Serous Ovarian Carcinoma ◽  
Number Of Patients

AbstractIn the early 2000s a two-tier grading system was introduced for serous ovarian cancer. Since then, we have increasingly come to accept that low-grade serous ovarian carcinoma (LGSOC) is a separate entity with a unique mutational landscape and clinical behaviour. As less than 10% of serous carcinomas of the ovary are low-grade, they are present in only a small number of patients in clinical trials for ovarian cancer. Therefore the current treatment of LGSOC is based on smaller trials, retrospective series, and subgroup analysis of large clinical trials on ovarian cancer. Surgery plays a major role in the treatment of patients with LGSOC. In the systemic treatment of LGSOC, hormonal treatment and targeted therapies seem to play an important role.

scholarly journals Endoscopic adrenalectomy

1998 ◽  
Vol 44 (3) ◽  
pp. 49-53 ◽  
Author(s):  
P. S. Vetshev ◽  
L. I. Ippolitov ◽  
D. I. Gabaidze
Keyword(s):  
Clinical Trials ◽  
Endoscopic Surgery ◽  
Technological Progress ◽  
The Past ◽  
Endoscopic Adrenalectomy ◽  
Endoscopic Video ◽  
Number Of Patients

The widespread use of endoscopic surgery over the past 10 years is primarily associated with scientific and technological progress, the improvement of endoscopic video equipment, special tools necessary for ultra-precise operating techniques. Some laparoscopic surgeries have already been recognized by experts and are the method of choice in the treatment of a large number of patients, others are still at the stage of clinical trials and a set of sufficient observations to generalize [2, 10, 47].

scholarly journals Methodological Characteristics of Clinical Trials Supporting the Marketing Authorisation of Advanced Therapies in the European Union

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Iglesias-Lopez ◽  
Antònia Agustí ◽  
Antonio Vallano ◽  
Merce Obach
Keyword(s):  
European Union ◽  
Clinical Trials ◽  
Added Value ◽  
Life Cycle Approach ◽  
The European Union ◽  
Open Label ◽  
Advanced Therapy ◽  
Advanced Therapies ◽  
Number Of Patients ◽  
The Eu

Several advanced therapy medicinal products (ATMPs) have been approved in the European Union (EU). The aim of this study is to analyse the methodological features of the clinical trials (CT) that supported the marketing authorization (MA) of the approved ATMPs in the EU. A systematic review of the characteristics of pivotal CT of ATMPs approved in the EU until January 31st, 2021 was carried out. A total of 17 ATMPs were approved and 23 CT were conducted to support the MA (median, 1, range, 1–3). Of those studies, 8 (34.78%) were non-controlled and 7 (30.43%) used historical controls. Only 7 (30.4%) were placebo or active-controlled studies. Among all CT, 21 (91.3%) were open-label and 13 (56.52%) had a single-arm design. To evaluate the primary endpoint, 18 (78.26%) studies used an intermediate and single variable. The median (IQR) number of patients enrolled in the studies was 75 (22–118). To date, ATMPs’ approval in the EU is mainly supported by uncontrolled, single-arm pivotal CT. Although there is a trend toward an adaptive or a life cycle approach, a switch to more robust clinical trial designs is expected to better define the benefit and the therapeutic added value of ATMPs.

Modafinil Augmentation for Residual Symptoms of Fatigue in Patients with a Partial Response to Antidepressants

2007 ◽  
Vol 41 (6) ◽  
pp. 1005-1012 ◽  
Author(s):  
Jenny Y Lam ◽  
Maisha Kelly Freeman ◽  
Marshall E Cates
Keyword(s):  
Clinical Trials ◽  
Data Extraction ◽  
Controlled Clinical Trials ◽  
Open Label ◽  
Double Blind ◽  
Residual Symptoms ◽  
Randomized Controlled ◽  
Manual Search ◽  
Number Of Patients ◽  
Residual Fatigue

OBJECTIVE: To evaluate the literature discussing the use of modafinil in the treatment of residual symptoms of fatigue in patients with depression. DATA SOURCES: PubMed (1966–March 2007) and International Pharmaceutical Abstracts(1970–March 2007) were searched using the key words modafinil and depression. A manual search of the reference section of the articles retrieved was conducted to identify articles not indexed in either of these sources. STUDY SELECTION AND DATA EXTRACTION: All articles published in English were evaluated. Studies were included if modafinil was used to treat patients with residual fatigue from depression and the effects were measured with validated fatigue subscales. DATA SYNTHESIS: One retrospective study, 5 open-label trials, and 2 randomized controlled clinical trials met the inclusion criteria for assessment of residual symptoms of fatigue as assessed by commonly used fatigue subscales after modafinil administration. Although improvement with fatigue has occurred with modafinil therapy, literature regarding the topic is limited by the lack of well-controlled clinical trials. Modafinil does appear to improve residual fatigue with depression as evidenced by open-label trials; however, the efficacy of this agent has not been duplicated in randomized controlled trials. The open-label trials that have been conducted often had no comparator and a small number of patients. In addition, outcome measures used in the studies were not consistent between trials. Modafinil appears to be well tolerated, with the main adverse effects being headache and nausea. CONCLUSIONS: Open-label trials indicate that modafinil may be effective in ameliorating fatigue associated with depression; however, this effect has not been reproduced in randomized, double-blind, placebo-controlled clinical trials. Therefore, the use of modafinil for the treatment of residual fatigue is not recommended due to the lack of reproducible data of its efficacy. Long-term, adequately powered clinical trials should be conducted to determine its place in therapy.

scholarly journals Bioactive Prenyl- and Terpenyl-Quinones/Hydroquinones of Marine Origin †

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 292 ◽  
Author(s):  
Pablo García ◽  
Ángela Hernández ◽  
Arturo San Feliciano ◽  
Mª Castro
Keyword(s):  
Secondary Metabolites ◽  
Marine Organisms ◽  
Chemical Diversity ◽  
Rich Source ◽  
Pharmacological Properties ◽  
Active Compounds ◽  
Marine Origin ◽  
Synthetic Approaches

The sea is a rich source of biological active compounds, among which terpenyl-quinones/hydroquinones constitute a family of secondary metabolites with diverse pharmacological properties. The chemical diversity and bioactivity of those isolated from marine organisms in the last 10 years are summarized in this review. Aspects related to synthetic approaches towards the preparation of improved bioactive analogues from inactive terpenoids are also outlined.

The incidence of occult endocrinopathies in patients with cancer undergoing immunotherapy in community practice.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14571-e14571
Author(s):  
Ahmed Abdalla ◽  
Aditi Singh ◽  
Hussein Gharib ◽  
Benjamin Huber ◽  
Sindhu Janarthanam Malapati ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Testosterone Level ◽  
Single Agent ◽  
Laboratory Data ◽  
Endocrine Function ◽  
Hormone Levels ◽  
Primary Indication ◽  
Number Of Patients ◽  
The Mean ◽  
Stimulating Hormone

e14571 Background: Immune checkpoint blockade (IO) can induce inflammation of the pituitary, thyroid or adrenal glands. This usually results in non-specific symptoms such as headache, low-energy, nausea and vomiting, which can be difficult to differentiate from symptoms associated with cancer and therapy-related symptoms. Therefore, the exact incidence of endocrinopathies is exceedingly difficult to estimate in community practices. Also, the variable methods of assessment, diagnosis, and monitoring used in different clinical trials make it challenging to precisely measure the incidence of endocrinopathies. Methods: This is a single-center retrospective chart review of patients diagnosed with cancer receiving immunotherapy for cancer treatment who had routine hormone levels checked during their treatment. Data collected includes tumor types and the types of IO agents used. Laboratory data collected included thyroid-stimulating hormone (TSH), testosterone level, follicular stimulating hormone (FSH), luteinizing hormone (LH), cortisol levels. Results: In total, 75 patients were included in the study. The primary indication for IO was lung cancer in 43 patients (57%), genitourinary tumors (12%), melanoma (12%) and head & neck cancers (5.3%). Single-agent nivolumab (39 patients) was the most common IO agent used followed by single-agent pembrolizumab (22 patients), ipilimumab (11 patients), atezolizumab (3 patients), avelumab (1 patient) (There was one patient who got nivolumab initially and then pembrolizumab). Nine patients were treated with ipilimumab/nivolumab combination. The mean number of cycles received was 9.1. The total number of patients who developed at least one abnormal hormone level was 57(76%), with 33 out of 74 (45%) patients had at least one abnormal TSH, 29 out of 44 (66%) patients had at least one abnormal testosterone level, 10 out of 49 (20.4%) patients had at least one abnormal FSH and/or LH level, 36 out of 52 (69%) patients had at least one abnormal cortisol level. The mean number of days from starting IO to develop the first abnormal laboratory result was 106 days. Conclusions: The incidence of endocrinopathy was significantly high in patients receiving IO in this study, which is higher than what is reported in previous clinical trials. This could be due to frequent testing in asymptomatic patients and strict laboratory cut-off values which is not always clinically meaningful. This finding may highlight the importance of routine monitoring of the endocrine function during IO treatment. Routine measurement of hormone levels can detect asymptomatic endocrinopathy which may warrant further work-up and treatment. These findings should be validated in a larger prospective study.

Abstract P72: Pattern of Deactivation of Implantable Cardioverter Defibrillator in Inpatient Hospice Units

2011 ◽  
Vol 4 (suppl_1) ◽  
Author(s):  
Umashankar Lakshmanadoss ◽  
Lohith Reddy ◽  
Saadia Sherazi ◽  
Abeer Anabtawi ◽  
Michael DiSalle ◽  
...  
Keyword(s):  
End Of Life ◽  
Hospice Care ◽  
Metastatic Cancer ◽  
Care Center ◽  
Sudden Cardiac Arrest ◽  
Shock Therapy ◽  
Implantable Cardioverter Defibrillators ◽  
Icd Implantation ◽  
Number Of Patients ◽  
Icd Shock

Background: There have been an increasing number of patients receiving implantable cardioverter defibrillators (ICDs) over the last decade. Although ICDs prevent arrhythmic death, patients may still develop other terminal illnesses, or progression of underlying heart failure. ICD- delivered shocks are associated with significant pain, anxiety and reduced quality of life. Therefore for this population of patients, it may become undesirable to receive shock therapy nearing the end of life. We reviewed the practices for ICD deactivation on a series of patients admitted to a hospice center. We hypothesized that for patients with ICDs, the frequency for ICD deactivation at end of life would be low. Methods: In this retrospective study we reviewed records of patients with ICDs who were admitted to the Hildebrandt Hospice Care Center, an inpatient hospice facility, in Rochester NY from January 2005 to December 2009. Information regarding patient's demographics, indications for ICD implantation, deactivation of ICD (frequency, location) and history of shock in hospice care was recorded. Results: We identified 32 patients who were admitted to inpatient hospice with ICDs for primary prevention of sudden cardiac arrest. The mean age was 78 + 9 years and 23 out of 32 (72%) were male. Sixteen patients had metastatic cancer, 8 patients had sepsis, 4 patients had stroke, 3 patients had renal disease and one patient had liver disease. Twenty (62%) patients had their ICD deactivated in the hospital before transferring to inpatient hospice. Nine (28%) patients were transferred to the center without ICD deactivation. Among these patients, 3 (10%) received ICD shock while in hospice and subsequently died in the center (average 2 days after receiving the shock). Three (10%) patients refused to have their ICD deactivated. Out of these three patients, two died in the hospice center while one patient was discharged home and none of them had ICD shock during hospice admission. Conclusion: The discussion about ICD deactivation should be initiated in terminally ill patients who are opting for hospice care for end of life care. Deactivating the device allows patients to die without the discomfort of electric shocks.

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