Pharmacy Workload in Clinical Trial Management: A Preliminary Complexity Assessment Tool for Sponsored Oncology and Haematology Trials.

Investigational drug services need to be organised in a structured approach, especially for sites with a large number of ongoing clinical trials. The aim of this study was to develop a tool to assess the complexity of pharmacy involvement in a sponsored oncology clinical trial. Categorisation into ordinal complexity categories was used to assess the complexity of the clinical trials for consistent pharmacy grant applications. The 15 items of the tool were divided into three sections, and individual item scores were agreed upon among four pharmacists with experience in the conduct of clinical trials at two different centres. A final version of the tool, named Pharm-CAT, was approved. The pharmacists were instructed to use Pharm-CAT to assign a score to each new sponsored trial. To determine the cut-offs for the complexity categories, the scores were sorted in ascending order and the cut-offs corresponding to the first and third tertiles of the score distribution were selected. To verify the reproducibility of the results, Pharm-CAT was applied by two pharmacists independently for each trial. Pharm-CAT proved to be user-friendly. Sixty clinical trials were evaluated and a total of 120 scores were recorded. Low-complexity scores ranged from 0 to 19, medium-complexity scores ranged from 20 to 25, and high-complexity scores were 26 or higher. The average score recorded was 22.88 points. Prospective multicentre validation of Pharm-CAT is needed to confirm its applicability.

Emerging Toxicities of Antibody-Drug Conjugates for Breast Cancer: Clinical Prioritization of Adverse Events from the FDA Adverse Event Reporting System.

BACKGROUND: Antibody-drug conjugates (ADCs) are gaining widespread use in the treatment of breast cancer, although toxicity remains an underexplored issue in the real-world clinical setting. Individual case safety reports collected in large pharmacovigilance databases can advance our knowledge on their safety profile in routine clinical practice. OBJECTIVE: We prioritized adverse events (AEs) reported with ADCs approved for breast cancer using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We assessed clinical priority of AEs reported in FAERS (February 2013-March 2022) for trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) by attributing a score to each AE disproportionally reported with ADCs. Four criteria were assessed: clinical relevance, reporting rate, reported case fatality rate, and stability of disproportionality signals (consistency of the reporting odds ratio across multiple analyses using three different comparators). RESULTS: We retained 6589 reports (77.4% referring to T-DM1 as suspect), and 572 AEs generated a disproportionality signal in at least one analysis. The majority of these AEs (62%) were classified as moderate clinical priorities (e.g., interstitial lung disease with T-DXd, thrombocytopenia, peripheral neuropathy with T-DM1, febrile neutropenia, and large intestine perforation with SG). Three AEs emerged as high clinical priorities (6 points): septic shock and neutropenic colitis with SG (N = 8 and 13, with median onset 13 and 10 days, respectively), without co-reported immunosuppressive agents; and pulmonary embolism with T-DM1 (N = 31, median onset 109 days, 52% with reported metastasis). CONCLUSION: The heterogeneous spectrum of post-marketing toxicities for ADCs used in breast cancer, as emerging from the FAERS, is largely in line with preapproval evidence. Although causality cannot be proved, we call for increased awareness by oncologists on potential serious unexpected reactions, including early onset of septic shock and neutropenic colitis with SG, and late emergence of pulmonary embolism with T-DM1.

Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice.

The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes-mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology.

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Lung Cancer.

BACKGROUND: Lung cancer is the most frequent cause of cancer-related death. In the last decades, the introduction of targeted therapies and more recently, of immunotherapy, has led to significant improvements in different outcomes of this malignant neoplasm. OBJECTIVE: The present review provides a balanced overview of most recent targeted therapies and immunotherapies patented for the treatment of lung cancer. METHODS: An extensive scientific literature and patent databases search were performed to identify peerreviewed studies containing information on recently patented drugs for the treatment of lung cancer, with a particular focus on their safety data and recently patented combinations. RESULTS: The development of therapies directed to different pathways involved in the tumor angiogenesis, proliferation, and metastasis has transformed the clinical practice of lung malignancies. Several clinical trials have shown an improvement in terms of progression-free survival and overall survival in patients with advanced/metastatic lung cancer. Safety data, extracted from clinical trials and from the WHO global database of adverse drug reactions (VigiAccessTM database), show that recently patented drugs for the treatment of lung cancer are well-tolerated and most of the adverse events reported are mild to moderate. CONCLUSION: Currently, a consistent number of new drugs and combinations have been introduced for the treatment of patients with advanced-stage lung cancer. Safety data remain essential to better assess the long-term risk/benefit ratio of these valuable emerging therapies. The new patents' development could provide further significant improvements for lung cancer treatment.

Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. The aim of this study was to analyze the long-term outcomes for obese patients undergoing LT, including a noninvasive weight loss program and combined LT and sleeve gastrectomy (SG). Since 2006, all patients referred for LT with a body mass index (BMI) ≥35 kg/m2 were enrolled. Patients who achieved weight loss (BMI <35) underwent LT alone, and those who did not underwent simultaneous LT + SG. Analysis of long-term outcomes for patients ≥3 years posttransplant was performed. Since 2006, there were 36 in the weight loss intervention (LT cohort) and 13 in the LT + SG cohort with >3 years of follow-up, whereas overall, a total of 29 patients underwent LT + SG. Patients in the LT cohort had less severe obesity at enrollment (40.0 ± 2.7 vs. LT + SG cohort 46.0 ± 4.5; P < 0.001). In the LT cohort, 83.3% (30 of 36) achieved >10% loss in total body weight (TBW) pre-LT. Three years posttransplant, 29.4% of patients in the LT cohort maintained >10% loss in TBW, whereas 100% of the LT + SG patients did (P < 0.001). Patients who underwent LT + SG maintained a significantly higher percentage of total body weight loss after 3 years of follow-up (LT cohort 3.9 ± 13.3% vs. LT + S G cohort 34.8 ± 17.3%; P < 0.001). Patients in the LT + SG also had a lower prevalence of hypertension, insulin resistance, and hepatic steatosis and required fewer antihypertensive medications and lipid agents at last follow-up. CONCLUSION: Whereas weight loss before transplantation was achieved by obese patients, weight regain was common in the LT cohort. Combined LT + SG resulted in more effective and more durable weight loss, as well as fewer metabolic complications at last follow-up. (Hepatology 2018).

Amatuximab and novel agents targeting mesothelin for solid tumors.

Mesothelin (MSLN) is considered a promising target for cancer therapy. Originally extracted in 1992 after the immunization of mice with a human ovarian cancer (OC) cell line and cloned in 1996, MSLN seems to be involved in cell adhesion and metastasis. MSLN is prevalent in mesothelia tissues but is expressed in several human cancers, such as OC, pancreatic cancer, mesothelioma, and lung cancer. Amatuximab (MORAb-009) is a mouse-human chimeric monoclonal antibody with a selective affinity for MSLN. The principal mechanism of action comprises inhibition of binding of MSLN with the antigen CA125/MUC16. The highest phase of development is actually a Phase II trial (MORAb-009-201, Europe). In this review, we describe the mechanism of action of amatuximab and other MSLN-targeting novel drugs, along with a discussion about the expected efficacy, safety, and toxicity of this promising group of agents and implications for future research and clinical practice.

Safety and efficacy evaluation of albumin-bound paclitaxel.

INTRODUCTION: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free formulation of paclitaxel, which was developed to avoid toxicities associated with Cremophor EL® vehicle used in solvent-based paclitaxel. It is approved as monotherapy for treatment of metastatic breast cancer (MBC) in Europe and the US; in combination therapy for non-small-cell lung cancer (NSCLC) and for first-line treatment of advanced pancreatic cancer (PC) only in the US. The European Medicines Agency has recently released only a positive opinion for use of nab-paclitaxel in PC. AREAS COVERED: This review reports the clinical findings and the safety data of nab-paclitaxel for MBC, NSCLC and PC. EXPERT OPINION: In MBC, nab-paclitaxel has demonstrated a good safety and an efficacy profile compared with other taxanes, but no strong data on overall survival are available. Considering the role of markers or predictive factors for nab-paclitaxel effectiveness in the metastatic setting would be useful. In PC, nab-paclitaxel and gemcitabine represent a new therapeutic choice with significant improvement in survival. In a Phase III study with NSCLC patients, nab-paclitaxel showed better results in a subgroup of patients with squamous histology, for whom results with conventional therapies are still poor and improved therapeutic options are needed.

Antidepressants for patients with tinnitus.

BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 4, 2006 and previously updated in 2009.Tinnitus is described as the perception of sound or noise in the absence of real acoustic stimulation. It has been compared with chronic pain, and may be associated with depression or depressive symptoms which can affect quality of life and the ability to work. Antidepressant drugs have been used to treat tinnitus in patients with and without depressive symptoms. OBJECTIVES: To assess the effectiveness of antidepressants in the treatment of tinnitus and to ascertain whether any benefit is due to a direct tinnitus effect or a secondary effect due to treatment of concomitant depressive states. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; PsycINFO; CINAHL; Web of Science; BIOSIS; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 5 January 2012. SELECTION CRITERIA: Randomised controlled clinical studies of antidepressant drugs versus placebo in patients with tinnitus. DATA COLLECTION AND ANALYSIS: Two authors critically appraised the retrieved studies and extracted data independently. Where necessary we contacted study authors for further information. MAIN RESULTS: Six trials involving 610 patients were included. Trial quality was generally low. Four of the trials looked at the effect of tricyclic antidepressants on tinnitus, investigating 405 patients. One trial investigated the effect of a selective serotonin reuptake inhibitor (SSRI) in a group of 120 patients. One study investigated trazodone, an atypical antidepressant, versus placebo. Only the trial using the SSRI drug reached the highest quality standard. None of the other included trials met the highest quality standard, due to use of inadequate outcome measures, large drop-out rates or failure to separate the effects on tinnitus from the effects on symptoms of anxiety and depression. All the trials assessing tricyclic antidepressants suggested that there was a slight improvement in tinnitus but these effects may have been attributable to methodological bias. The trial that investigated the SSRI drug found no overall improvement in any of the validated outcome measures that were used in the study although there was possible benefit for a subgroup that received higher doses of the drug. This observation merits further investigation. In the trial investigating trazodone, the results showed an improvement in tinnitus intensity and in quality of life after treatment, but in neither case reached statistical significance. Reports of side effects including sedation, sexual dysfunction and dry mouth were common. AUTHORS' CONCLUSIONS: There is as yet insufficient evidence to say that antidepressant drug therapy improves tinnitus.

Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series.

Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients. Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations.

Cancer vaccines in phase II/III clinical trials: state of the art and future perspectives.

The topic of this review covers a very important branch of cancer research, cancer vaccination. The growing knowledge in tumor immunology has evolved rapidly, starting from nonspecific generic stimulation of the immune system to more specific approaches based on the availability of tumor antigens. The review covers molecular and cell biology, and pharmaceutical technology of cancer vaccines. Particularly, it is aimed at highlighting the results of cancer vaccines from phase II and III clinical trials, an issue that is of relevance to better understand how cancer vaccines can successfully complement antitumor therapy, including conventional chemotherapy and the recently developed target-based drugs.

mTOR pathway and mTOR inhibitors as agents for cancer therapy.

Research into mTOR, mammalian Target Of Rapamycin as an important drug target continues to be extremely interesting, both in terms of the increased molecular knowledge being acquired at the basis of various human diseases, and also for possible applications in drug cancer therapy. The mTOR signaling system plays a key role in several transduction pathways that are necessary for cell cycle progression and cellular proliferation. Drugs known as mTOR inhibitors have been included in ongoing and in recently completed cancer trials. New insights into the mTOR signaling system are helping to clarify the functionality of key mTOR components, and especially their possible role in apoptosis, angiogenesis and tumor progression. Three other molecules, already approved for therapeutic use and being commercialized (Everolimius, Temsirolimus and Zotarolimus) are added to Rapamycin (also known as Sirolimus), the parent drug of the mTOR inhibitors. Of these, only Temsirolimus is currently approved in the treatment of renal cell carcinoma, while the others are approved for organ transplant rejection and coronary artery restenosis. There are at least 10 other molecules currently under development for clinical and preclinical studies. This review offers an updated synopsis of the mTOR signaling system, in particular as regards relevant aspects of cancer research, looks at the known mTOR inhibitors and gives a systematic vision of current trials for each individual molecule subject to clinical investigation.

Ruthenium(III) dimethyl sulfoxide pyridinehydroxamic acid complexes as potential antimetastatic agents: synthesis, characterisation and in vitro pharmacological evaluation.

Reaction of 3-pyridinehydroxamic acid and 4-pyridinehydroxamic acid (3-pyha and 4-pyha) with either [NBu4][RuCl4(dmso-S)2] or [(dmso)2H][RuCl4(dmso-S)2] (dmso is dimethyl sulfoxide) in acetone afforded three new ruthenium(III) dimethyl sulfoxide pyridinehydroxamic acid complexes: [NBu4][trans-RuCl4(dmso-S)(4-pyha)] x CH3CO CH3 (1), [3-pyhaH][trans-RuCl4(dmso-S)(3-pyha)] (2) and [4-pyhaH][trans-RuCl4(dmso-S)(4-pyha)] (3). The solid-state structure of [NBu4][trans-RuCl4(dmso-S)(4-pyha)] x CH3COCH3 (1) was determined by X-ray crystallography. 2 and 3 were pharmacologically evaluated for their in vitro cytotoxicity, their ability to inhibit cell invasion and their gelatinase activity. 2 and 3 were devoid of cytotoxicity against the cell lines tested. 2 inhibited invasion of the highly invasive MDA-MB-231 cells to a much greater extent than 3. Contrary to expectations, neither 2 nor 3 had any inhibitory effect on matrix metalloproteinase (MMP) production and/or activity and in fact 3 was found to enhance the production and/or activity of both MMP-2 and MMP-9.