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Side Effects of Targeted Therapy
Side effects of Targeted Therapy Joanne Bird Clare Warnock NIHR Research Fellow Senior Project Nurse Types of Anti Cancer Therapy Biological Therapies Cytotoxic Drugs • Hormone therapies Ongoing research (Chemotherapy) • Goserelin/Zoladex.® • Anti cancer vaccines • Antibiotics • Tamoxifen • Blood cell growth factors • Monoclonal Antibodies • Blood vessel growth • Antimetabolites • Herceptin blockers • Retuximab • IFN/IL2 • Alkylating agents • Bevacizumab (avastin) • Gene therapy • Radioactive substance • Vinca Alkaloids • Cancer growth inhibiters carriers (conjugated MABs) – Tyrosine Kinase Inhibitors • Anthracyclines – Proteasome inhibitors • Drug carriers – mTOR inhibitors – PI3K inhibitors – Histone deacetylase inhibitors – Hedgehog pathway blockers • Pro cytotoxic Drugs • Capecitabine Tyrosine Kinase Inhibitors • How many do you know!!!!! TKIs • Afatanib • Imatinib • Axitinib • Lapatinib • Bosutinib • Nilotinib • Crizotinib • Pazopanib • Dabrafenib • Regorafenib • Dasatinib • Sorafenib • Erlotinib • Sunitinib • Gefitinib • Trametinib Principles • Growth factor receptors play a role on the normal processes of cell growth and development. – In some cancers these growth receptors are over- expressed leading to unregulated cell growth. • Molecular pathways involved in cancer cell proliferation are identified • Drugs are developed to act on these pathways Symptom grading • Standardised assessment – objective – My small and your small may be different! • Effective communication and documentation • Accurate evaluation of new treatments in -
Regulation of Glucose Metabolism in Muscles from Dexamethasone Treated Rats
Regulation of Glucose Metabolism in Muscles from Dexamethasone Treated Rats Effect of insulin, adrenaline and contraction Anders Rasmushaugen Master thesis in pharmacology for the degree Master of Pharmacy Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences UNIVERSITY OF OSLO Spring 2009 2 Regulation of Glucose Metabolism in Muscles from Dexamethasone Treated Rats Effect of insulin, adrenaline and contraction Anders Rasmushaugen The thesis was conducted between July 2008 and May 2009 at the Department for Work-related Muscoskeletal Complaints, National Institiute of Occupational Health (STAMI) Master thesis in pharmacology for the degree Master of Pharmacy Departement of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences UNIVERSITY OF OSLO Advisors Senior scientist Dr. scient Jørgen Jensen Professor Arild C Rustan 3 Preface This thesis has been my biggest challenge in my years at the Institute of Pharmacy, and I want to thank those who have supported me during it. My advisor, Jørgen Jensen, has directed me through the work of this thesis and I greatly appreciate his efforts. Jørgen is a man that involves himself in his work, I hope this eagerness carries on. Special thanks are directed to the ones of you helping me with the practical work involved in the various analyses. Ada Ingvaldsen, Astrid Bolling and Jorid Thrane Stuenæs have always been accessible for questions as well as discussions. I will also thank STAMI in general for making this thesis possible. The student environment on the 5th floor has been comforting and a source of great fun as well as discussions related the studies. -
Statistical Analysis Plan (SAP)
Statistical Analysis Plan (SAP) Protocol Title: A Phase IIa, two-part, randomised, multi-centre, multinational, double-blind, placebo-controlled, parallel group study to compare the efficacy and safety of BCT197 when added on to standard of care for the treatment of acute respiratory exacerbations of chronic obstructive pulmonary disease (COPD) requiring hospitalisation in adults Protocol Number: MBCT206 Protocol Version, Date Final V1.0, 05 November 2015 Final V2.0 (Amendment 1), 23 December 2015 Final V3.0 (Amendment 2), 10 March 2016 Final V4.0 (Amendment 3), 26 May 2016 Final V5.0 (Amendment 4), 08 November 2016 ICON ID: 3082/0004 Document Version, Date: FINAL 1.0, 07 September 2017 FINAL 2.0, 16 November 2017 Prepared by: ICON Clinical Research Services On behalf of: Mereo BioPharma 1 Ltd Statistical Analysis Plan Version: FINAL 2.0, Date:16 November 2017 Protocol Number: MBCT206 Page 1 of 112 Statistical Analysis Plan (SAP) Confidentiality statement: The information provided in this document is strictly confidential. The recipients of the SAP must not disclose the confidential information . contained within this document or any related information to other persons without the permission of the sponsor. In addition, the recipients of the SAP must keep this confidential document in a . controlled environment which prevents unauthorized access to the document. Statistical Analysis Plan Version: FINAL 2.0, Date:16 November 2017 Protocol Number: MBCT206 Page 2 of 112 Statistical Analysis Plan (SAP) SIGNATURE PAGE Prepared at ICON Clinical Research by: Date (DD Mmm YYYY) Reviewed at ICON Clinical Research by: Date (DD Mmm YYYY) Approved at Mereo BioPharma 1 Ltd by: Date (DD Mmm YYYY) Statistical Analysis Plan Version: FINAL 2.0, Date:16 November 2017 Protocol Number: MBCT206 Page 3 of 112 Statistical Analysis Plan (SAP) REVISION HISTORY Version/Date Version name Section Changes implemented Version 1.0/ Initial approved N/A N/A 07-Sep-2017 version 7.1.4.13 Clinical treatment failure Medical review clarification added. -
Cancer Diagnosis Y Tumor Stage Second Emergency Visits…
25th Congress of the EAHP Abstract Number: 4CPS-282 ATC code: L01 - Cytostatics EPIDEMIOLOGY AND CLINICAL COURSE OF PATIENTS WITH CANCER DIAGNOSED WITH SARS-COV-2 INFECTION I. Taladriz Sender, F.J. García Moreno, C. Villanueva Bueno, J. Vicente Valor, J.L. Revuelta Herrero, R. Collado Borrell, V. Escudero Villaplana, E. González-Haba Peña, Sanjurjo Sáez M Servicio de Farmacia. Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM). Madrid, España OBJECTIVES Background: Cancer patients are supposed to be a vulnerable population for SAR-CoV-2 infection. OBJECTIVE: to describe the epidemiology and clinical course of patients with cancer infected with SARS- Cov-2 who were attended in the hospital. METHODS • Design: Retrospective, observational study conducted in cancer patients who were attended in a tertiary hospital for SARS-CoV-2 infection during the period 03/01/2020-31/05/2020. • Demographic and clinical variables were analyzed: comorbidities, tumor diagnosis, tumor stage and whether they had received anticancer treatment in the last month (active treatment). • The clinical course was evaluated through: ✓ Hospital admission ✓ Pneumonia and oxygen therapy requirements ✓ Development of acute respiratory distress syndrome (ARDS) ✓ Admission to ICU and mortality rate. RESULTS ✓ 60.7% Patients had active cancer therapy 112 patients Graph 1. Cancer treatments 59.8% men 3% Chemotherapy Mean age = 67±13.4years 7% 94.6% Caucasian, 4.4% latino Hormonal Comorbidities 16% 42% treatment Targeted therapy ▪ Smoking status: 61.6% non-smokers, 25% ex-smokers, 13.4% current smokers. Immunotherapy ▪ Obesity = 11.6% 32% Radiotherapy ▪ Arterial hypertension = 57.1% ▪ Cardiovascular disease = 34.8% Upon admission: ▪ DM II = 32.1% ✓ Pneumonia = 85.7% // Lymphopenia = 59.9% // p02< 90% = 31.3% ▪ COPD = 21.4% Graph 2. -
Evaluating Onco-Geriatric Scores and Medication Risks to Improve Cancer Care for Older Patients
Evaluating onco-geriatric scores and medication risks to improve cancer care for older patients Dissertation zur Erlangung des Doktorgrades (Dr. rer. nat.) der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von IMKE ORTLAND aus Quakenbrück Bonn 2019 Angefertigt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn. Diese Dissertation ist auf dem Hochschulschriftenserver der ULB Bonn elektronisch publiziert. https://nbn-resolving.org/urn:nbn:de:hbz:5-58042 Erstgutachter: Prof. Dr. Ulrich Jaehde Zweitgutachter: Prof. Dr. Andreas Jacobs Tag der Promotion: 28. Februar 2020 Erscheinungsjahr: 2020 Danksagung Auf dem Weg zur Promotion haben mich viele Menschen begleitet und in ganz unterschiedlicher Weise unterstützt. All diesen Menschen möchte ich an dieser Stelle ganz herzlich danken. Mein aufrichtiger Dank gilt meinem Doktorvater Prof. Dr. Ulrich Jaehde für das in mich gesetzte Vertrauen, sowie für die Überlassung dieses spannenden Dissertationsthemas. Die uneingeschränkte Unterstützung, wertvollen Diskussionen und die mitreißende Begeisterung für die Wissenschaft haben mich während aller Phasen der Dissertation stets motiviert, unterstützt und sehr viel Wertvolles gelehrt. Prof. Dr. Andreas Jacobs danke ich herzlich für die Initiierung dieses interessanten Projekts, für die stetige Begeisterung und Unterstützung, sowie für das mir entgegengebrachte Vertrauen. Die ausgezeichnete Zusammenarbeit mit dem Johanniter Krankenhaus Bonn hat ganz maßgeblich zum Gelingen dieser Arbeit beigetragen. Auch danke ich Prof. Dr. Andreas Jacobs herzlich für die Bereitschaft, das Koreferat dieser Arbeit zu übernehmen. Ebenfalls danke ich herzlich Prof. Dr. Yon-Dschun Ko für seine fortwährende Motivation und seinen Einsatz, sowie für das mir geschenkte Vertrauen, dieses Projekt am Johanniter Krankenhaus zu realisieren. Ebenfalls danke ich Prof. -
Medication Risks in Older Patients with Cancer
Medication risks in older patients with cancer 1 Medication risks in older patients (70+) with cancer and their association with therapy-related toxicity Imke Ortland1, Monique Mendel Ott1, Michael Kowar2, Christoph Sippel3, Yon-Dschun Ko3#, Andreas H. Jacobs2#, Ulrich Jaehde1# 1 Institute of Pharmacy, Department of Clinical Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany 2 Department of Geriatrics and Neurology, Johanniter Hospital Bonn, Johanniterstr. 1-3, 53113 Bonn, Germany 3 Department of Oncology and Hematology, Johanniter Hospital Bonn, Johanniterstr. 1-3, 53113 Bonn, Germany # equal contribution Corresponding author Ulrich Jaehde Institute of Pharmacy University of Bonn An der Immenburg 4 53121 Bonn, Germany Phone: +49 228-73-5252 Fax: +49-228-73-9757 [email protected] Medication risks in older patients with cancer 2 Abstract Objectives To evaluate medication-related risks in older patients with cancer and their association with severe toxicity during antineoplastic therapy. Methods This is a secondary analysis of two prospective, single-center observational studies which included patients ≥ 70 years with cancer. The patients’ medication was investigated regarding possible risks: polymedication (defined as the use of ≥ 5 drugs), potentially inadequate medication (PIM; defined by the EU(7)-PIM list), and relevant potential drug- drug interactions (rPDDI; analyzed by the ABDA interaction database). The risks were analyzed at two different time points: before and after start of cancer therapy. Severe toxicity during antineoplastic therapy was captured from medical records according to the Common Terminology Criteria for Adverse Events (CTCAE). The association between Grade ≥ 3 toxicity and medication risks was evaluated by univariate regression. -
Protein Kinase C As a Therapeutic Target in Non-Small Cell Lung Cancer
International Journal of Molecular Sciences Review Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer Mohammad Mojtaba Sadeghi 1,2, Mohamed F. Salama 2,3,4 and Yusuf A. Hannun 1,2,3,* 1 Department of Biochemistry, Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA; [email protected] 2 Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; [email protected] 3 Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA 4 Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Dakahlia Governorate, Egypt * Correspondence: [email protected] Abstract: Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. Citation: Sadeghi, M.M.; Salama, PKC isoforms α, ", η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates M.F.; Hannun, Y.A. Protein Kinase C with worse prognosis in NSCLC patients. -
Changing the Destiny of HER2 Expressing Solid Tumors
International Journal of Molecular Sciences Review Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors Alice Indini 1 , Erika Rijavec 1 and Francesco Grossi 2,* 1 Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; [email protected] (A.I.); [email protected] (E.R.) 2 Medical Oncology Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy * Correspondence: [email protected] or [email protected] Abstract: HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. -
Trastuzumab Deruxtecan for Metastatic HER2 - Positive Breast Cancer – Second Line
HEALTH TECHNOLOGY BRIEFING DECEMBER 2020 Trastuzumab deruxtecan for metastatic HER2 - positive breast cancer – second line NIHRIO ID 24202 NICE ID 10444 Developer/Company Daiichi Sankyo Ltd UKPS ID 655938 Licensing and market Currently in phase III clinical development. availability plans SUMMARY Trastuzumab deruxtecan is in clinical development for the treatment of adults with HER2- positive, unresectable and/or metastatic breast cancer who have previously been treated with trastuzumab and taxane. HER2-positive breast cancer is when the cancer tests positive for HER2 protein, which promotes the growth of cancer cells and tend to be more aggressive than other types of breast cancer. Metastatic breast cancer (stage IV) is when the cancer has spread beyond the breast and nearby lymph nodes to other organs in the body, while unresectable means that the cancer cannot be treated by surgery. Treatment of the disease often involves the use of anti-HER2 therapies, chemotherapy, or a combination of both. Trastuzumab deruxtecan consists of an anti-HER2 therapy (trastuzumab) and a chemotherapy agent (deruxtecan) combined as an antibody-drug conjugate. Trastuzumab deruxtecan is administered intravenously. It has been developed such that the trastuzumab specifically binds to cancer cells that are HER2-positive which provides a targeted delivery of deruxtecan inside cancer cells, which then acts to kill the cancer cells. This reduces systemic exposure to the chemotherapy with the potential to reduce associated toxicities and adverse effects. If licenced, trastuzumab deruxtecan could provide an additional second line treatment option for HER2-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab and taxane. This briefing reflects the evidence available at the time of writing and a limited literature search. -
Opportunities and Challenges in the Development of Kinase Inhibitor Therapy for Cancer
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Opportunities and challenges in the development of kinase inhibitor therapy for cancer Charles L. Sawyers1 Howard Hughes Medical Institute; Departments of Medicine, Molecular and Medical Pharmacology, and Urology; and Jonsson Cancer Center; David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA The success of the tyrosine kinase imatinib inhibitor notion of “kinase dependency” states in cancer cells and (Gleevec, STI571) in treating chronic myeloid leukemia the challenges inherent in recognizing these tumors in as well as other selected cancers has greatly increased the clinic. I also outline a general strategy for conducting optimism for the broader application of kinase inhibitor first-in-human, phase I clinical trials of kinase inhibitors therapy in cancer. To date, however, imatinib remains that includes molecular enrollment criteria and precise the only spectacularly successful example. Is it simply a biochemical and biological measures of drug action in matter of time before kinase inhibitors become more tumor cells so that subsequent decisions for clinical de- broadly useful? Or is chronic myeloid leukemia a unique velopment of a novel compound might be more in- disease that does not reflect the true genetic complexity formed. of other cancers? Here I address this question by sum- marizing the growing evidence that kinase inhibitor therapy works consistently and reliably against cancers Present -
Trastuzumab: a Picky Partner? □□ Commentary on Francia Et Al., P
Published OnlineFirst October 14, 2009; DOI: 10.1158/1078-0432.CCR-09-1917 CCR Translations Trastuzumab: A Picky Partner? □□ Commentary on Francia et al., p. 6358 Heather L. McArthur and Clifford A. Hudis Preclinical and clinical models of HER2-positive breast cancer show that human epider- mal growth factor receptor 2 (HER2)-targeted therapy with trastuzumab adds significant benefits and modest risks to conventional cytotoxic therapies. Building on this advance will likely depend on elucidation of relevant signaling pathways and mechanisms of action for effective HER2-targeted therapies. (Clin Cancer Res 2009;15(20):6311–3) In this issue of Clinical Cancer Research, Francia and colleagues with trastuzumab and why tumors that initially exhibit sensitivity explore pulsatile, maximally tolerated doses of cyclophospha- ultimately acquire apparent clinical resistance. On the other mide chemotherapy or the same drug using a daily low-dose hand, it is difficult to explain why trastuzumab in combina- schedule combined with the human epidermal growth factor tion with chemotherapy is active even after progression on receptor 2 (HER2)-targeted antibody trastuzumab in a preclin- trastuzumab (7). It is perhaps easier to explain activity in this ical model of HER2-positive breast cancer (1). One of the most treatment-refractory setting for a drug with a different mecha- notable developments in breast cancer translational research nism of anti-HER2 activity, such as lapatinib, a HER1- and has been the identification of the HER2-positive subset of hu- HER2-directed tyrosine kinase inhibitor (TKI), (the only other man breast cancers and the subsequent successful development HER2-targeted agent approved by the United States Food and of HER2-targeted therapies. -
PASS Information
PASS Information Title Cilostazol drug utilisation study Protocol version Version 2.3 identifier Date of last version of 5 November 2015 protocol EU PAS register number ENCEPP/SDPP/3596 http://www.encepp.eu/encepp/viewResource.htm?id=10426 Accessed 5 November 2015 Active substance Cilostazol, ATC code B01AC23, Platelet aggregation inhibitors excluding heparin Medicinal product Pletal, Ekistol Product reference UK/H/0291/001 and 002 Procedure number EMEA/H/A-31/1306 Marketing authorisation Otsuka Pharmaceutical Europe Ltd. holder(s) (MAH) Lacer S.A. Joint PASS No Research question and This study protocol was developed in the context of the European objectives Medicines Agency (EMA) referral (article 31 of Council Directive 2001/83/EC) on the risks and benefits of the use of cilostazol. The study objectives are to characterise patients using cilostazol according to demographics, comorbidity, comedications, and duration of treatment. In addition, the study will describe the dosing of cilostazol, the prescribing physician specialties, and the potential off-label prescribing. Country(-ies) of study Spain, United Kingdom, Germany, Sweden Author Jordi Castellsague, MD, MPH; Cristina Varas-Lorenzo, MD, MPH, PhD; Susana Perez-Gutthann, MD, MPH, PhD RTI Health Solutions Trav. Gracia 56 Atico 1 08006 Barcelona, Spain Telephone: +34.93.241.7766 Fax: +34.93.414.2610 E-mail: [email protected] CONFIDENTIAL 1 of 65 Marketing Authorisation Holder(s) Marketing authorisation Otsuka Pharmaceutical Europe Ltd. holder(s) Gallions Wexham Springs Framewood Road Wexham SL3 6PJ, UK Lacer S.A. Sardenya 350 08025 Barcelona Spain MAH contact person Dr Marco Avila Regional Vice President, Medical Europe Otsuka Pharmaceutical Europe Ltd EU QPPV Dr Achint Kumar Otsuka Europe Development and Commercialisation Limited (OEDC) Head of Medical Dr Sanjay Kapoor Compliance-Europe Otsuka Pharmaceutical Europe Ltd.