scholarly journals Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies

Thorax ◽  
2015 ◽  
Vol 70 (8) ◽  
pp. 748-756 ◽  
Author(s):  
Nicola A Hanania ◽  
Michael Noonan ◽  
Jonathan Corren ◽  
Phillip Korenblat ◽  
Yanan Zheng ◽  
...  
Keyword(s):  
Lung Function ◽  
Severe Asthma ◽  
Standard Of Care ◽  
Phase Iii ◽  
High Dose ◽  
Baseline Serum ◽  
Link Type ◽  
Asthma Exacerbations ◽  
Care Treatment ◽  
Standard Of Care Treatment

IntroductionIn a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity.MethodsLUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies.ResultsThe median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed.ConclusionsThese data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment.Trial registration numbersThe LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

scholarly journals One time a day mometasone/indacaterol fixed-dose combination versus two times a day fluticasone/salmeterol in patients with inadequately controlled asthma: pooled analysis from PALLADIUM and IRIDIUM studies

2021 ◽  
Vol 8 (1) ◽  
pp. e000819
Author(s):  
Kenneth Chapman ◽  
Richard van Zyl-Smit ◽  
Jorge Maspero ◽  
Huib A M Kerstjens ◽  
Yasuhiro Gon ◽  
...  
Keyword(s):  
Lung Function ◽  
Asthma Control ◽  
Pooled Analysis ◽  
Fixed Dose ◽  
High Dose ◽  
Asthma Control Questionnaire ◽  
Exacerbation Rate ◽  
Link Type ◽  
Asthma Exacerbations ◽  
Medium Dose

BackgroundDespite currently available standard-of-care inhaled corticosteroid (ICS)/long-acting β2-agonist therapies, a substantial proportion of patients with asthma remain inadequately controlled. This pooled analysis evaluated efficacy and safety of mometasone furoate/indacaterol acetate (MF/IND) versus fluticasone propionate/salmeterol xinafoate (FLU/SAL) in patients with inadequately controlled asthma.MethodsThis analysis included patients from PALLADIUM (NCT02554786) and IRIDIUM (NCT02571777) studies who received high-dose MF/IND (320/150 µg) or medium-dose MF/IND (160/150 µg) one time a day or high-dose FLU/SAL (500/50 µg) two times a day for 52 weeks. Reduction in asthma exacerbations, improvement in lung function, asthma control, and safety were evaluated for 52 weeks.ResultsIn total, 3154 patients (high-dose MF/IND, n=1054; medium-dose MF/IND, n=1044; high-dose FLU/SAL, n=1056) were included. High-dose MF/IND showed 26%, 22% and 19% reductions in rate of severe, moderate or severe, and all (mild, moderate and severe) exacerbations versus high-dose FLU/SAL, respectively, over 52 weeks (all, p<0.05). High-dose MF/IND improved trough FEV1 versus high-dose FLU/SAL at weeks 26 (Δ, 43 mL, p=0.001) and 52 (Δ, 51 mL, p<0.001). Reductions in asthma exacerbation rate and improvement in trough FEV1 with medium-dose MF/IND were comparable with high-dose FLU/SAL over 52 weeks. All treatments improved Asthma Control Questionnaire-7 score from baseline to 52 weeks with no difference between treatments. Safety was comparable between high-dose MF/IND and high-dose FLU/SAL.ConclusionsOne time a day, single-inhaler, high-dose MF/IND reduced asthma exacerbations and improved lung function versus two times a day, high-dose FLU/SAL in patients with inadequately controlled asthma. Similarly, improved outcomes were seen with one time a day, medium-dose MF/IND and two times a day, high-dose FLU/SAL, but at a lower ICS dose.

scholarly journals Under-Treatment of Older Patients with Newly Diagnosed Epithelial Ovarian Cancer Remains an Issue

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 952
Author(s):  
Lucy Dumas ◽  
Rebecca Bowen ◽  
John Butler ◽  
Susana Banerjee
Keyword(s):  
Ovarian Cancer ◽  
Older Women ◽  
Older Patients ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Standard Of Care ◽  
First Line ◽  
Care Treatment ◽  
Platinum Based Chemotherapy ◽  
Standard Of Care Treatment

Older women with ovarian cancer have disproportionately poorer survival outcomes than their younger counterparts and receive less treatment. In order to understand where the gaps lie in the treatment of older patients, studies incorporating more detailed assessment of baseline characteristics and treatment delivery beyond the scope of most cancer registries are required. We aimed to assess the proportion of women over the age of 65 who are offered and receive standard of care for first-line ovarian cancer at two UK NHS Cancer Centres over a 5-year period (December 2009 to August 2015). Standard of care treatment was defined as a combination of cytoreductive surgery and if indicated platinum-based chemotherapy (combination or single-agent). Sixty-five percent of patients aged 65 and above received standard of care treatment. Increasing age was associated with lower rates of receiving standard of care (35% > 80 years old versus 78% of 65–69-year-olds, p = 0.000). Older women were less likely to complete the planned chemotherapy course (p = 0.034). The oldest women continue to receive lower rates of standard care compared to younger women. Once adjusted for Federation of Gynaecology and Obstetrics (FIGO) stage, Eastern Cooperative Oncology Group (ECOG) performance status and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Optimisation of vulnerable patients utilising a comprehensive geriatric assessment and directed interventions to facilitate the delivery of standard of care treatment could help narrow the survival discrepancy between the oldest patients and their younger counterparts.

Do elderly women with endometrial cancer receive standard of care treatment?

2021 ◽  
Vol 162 ◽  
pp. S139
Author(s):  
Michelle Soloff ◽  
Aaron Nizam ◽  
Ariel Kredentser ◽  
Bethany Bustamante ◽  
Weiwei Shan ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Elderly Women ◽  
Standard Of Care ◽  
Care Treatment ◽  
Standard Of Care Treatment

scholarly journals STEM-24. RADIATION-INDUCED EXTRACELLULAR VESICLE (EV) RELEASE OF miR-603 PROMOTES IGF1-MEDIATED STEM CALL STATE IN GLIOBLASTOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii201-ii201
Author(s):  
Valya Ramakrishnan ◽  
Beibei Xu ◽  
Johnny Akers ◽  
Thien Nguyen ◽  
Jun Ma ◽  
...  
Keyword(s):  
Recipient Cell ◽  
Alkylating Agents ◽  
Acquired Resistance ◽  
Standard Of Care ◽  
Extracellular Vesicle ◽  
Cross Resistance ◽  
Dna Damages ◽  
Care Treatment ◽  
Standard Of Care Treatment ◽  
The Impact

Abstract INTRODUCTION Release of exosomes and extracellular vesicles (EV) by glioblastomas plays key roles in modulating the tumor microenvironment and therapeutic response. Studies to date have largely focused on the impact of EV and exosomes on the recipient cell. Here, we demonstrate that EV-mediated export of a master-regulatory miRNA has fate-determining impacts on the cell releasing the EVs. METHODS microRNA (miRNA) profiling was performed using clinical glioblastoma specimens from the same patients derived pre- and post-standard of care treatment. Mechanism mediating altered miRNA homeostasis were assessed. RESULTS While the levels of nearly all miRNAs remained unchanged after standard-of-care treatment, decreased levels of few, select miRNAs were observed, including miR-603. In response to ionizing radiation (IR), but not temozolomide (TMZ), glioblastoma cell lines exhibited a time-dependent decrease in miR-603 levels. While miR-603 biogenesis and degradation remained unchanged after IR, IR induced an increase in EV-mediated export of miR-603. Profiling of miR-603 targets revealed that miR-603 repressed the insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), genes required to maintain the cancer stem cell (CSC) state, as well as MGMT, the gene encoding a DNA repair protein that detoxifies temozolomide (TMZ) induced DNA damages. IR induced export of miR-603 de-repress IGF1/IGF1R to promote radiation resistance and de-repress MGMT to promote cross-resistance to TMZ and CCNU. Ectopic miR-603 expression overwhelmed cellular capacity for miR-603 export and synergized with the tumoricidal effects of IR and temozolomide (TMZ). CONCLUSIONS Radiation stimulated EV-mediated export of miR-603 to facilitate acquired resistance to IR and cross-resistance to DNA alkylating agents.

scholarly journals LS1 PRACTICAL APPLICATION AND UNDERLYING BIOLOGY OF TUMOR TREATING FIELDS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
Daniela Bota
Keyword(s):  
Immune Responses ◽  
Tumor Cells ◽  
Critical Role ◽  
High Mobility ◽  
Standard Of Care ◽  
Clinical Results ◽  
Phase Iii ◽  
Tumor Treating Fields ◽  
Standard Of Care Treatment ◽  
Stress Signals

Abstract Glioblastoma (GBM) is the most common and most aggressive form of brain cancer in adults. For decades, the mainstay of therapeutic intervention was based on surgical resection (when safely feasible), followed by radiotherapy (RT). In 2005, data from the landmark EORTC-NCIC trial changed the standard of care treatment for GBM. This phase III trial demonstrated a survival advantage for concomitant and adjuvant temozolomide (TMZ) chemotherapy when added to the standard course of radiation. In the group of patients assigned to radiation plus TMZ, median survival improved from 12.1 months (radiotherapy alone) to 14.6 months, but all the patient finally relapsed on TMZ. In 2015, Tumor Treating Fields (TTF, Optune) became the first FDA-approved device for the treatment of for newly diagnosed GBM. This approval was based on the EF-14 clinical trial results, in which nearly half of the patients treated with Optune in combination with maintenance temozolomide (TMZ) were alive at 2 years compared with 31% of people on TMZ alone. Optune utilize the natural electrical properties of dividing cancer cells to disrupt mitosis and provide continuous antimitotic action against progression of GBM. TTF-treated tumor cells can exit the process of mitosis aberrantly and release cellular stress signals, such as the endoplasmic reticulum chaperonin calreticulin (CRT) and high mobility group box 1 protein (HMGB1). CRT is important to induce antitumor immune responses because CRT inhibition decreases immunogenicity. HMGB1, an endogenous chromatin-associated protein released from dying tumor cells, also plays a critical role in the activation of HMGB1-mediated toll-like receptor 2 (TLR2) immune signaling. The presence of those signals may facilitate immune activation, and immunogenic induced cell death, and eventually result in tumor destruction. In this presentation, Daniela Bota, MD, PhD, will review the clinical results of Optune in the treatment of GBM, and will discuss the novel biological mechanisms underlying the effects of Optune in controlling tumor growth and promoting the immune responses in GBM.

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