Frequency Of Serious Adverse Events Research Articles

Abstract P1-12-10: Safety and efficacy of trastuzumab emtansine (T-DM1) in 399 patients with central nervous system metastases: Exploratory subgroup analysis from the KAMILLA study

Abstract Introduction T-DM1 treatment significantly improved overall survival and had a lower incidence of grade ≥3 adverse events (AEs) vs capecitabine plus lapatinib in patients (pts) with HER2-positive advanced breast cancer (BC) in the EMILIA study, including pts with treated, asymptomatic CNS metastases (mets). KAMILLA is an ongoing, single-arm, open-label, phase 3b global safety study of T-DM1 in pts with HER2-positive locally-advanced or metastatic BC (target n=2220). In this interim analysis we describe clinical characteristics, safety, and efficacy in pts with stable CNS mets at baseline (BL). Methods Eligible pts received prior HER2-directed therapy and chemotherapy and progressed on or after most recent treatment for advanced BC, or within 6 months of completing adjuvant therapy. Pts with asymptomatic CNS mets were eligible, including pts with stable CNS disease with prior radiation therapy. Pts received T-DM1 3.6 mg/kg every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression. This exploratory analysis describes pts with BL CNS mets. Median progression-free survival (PFS) was estimated using the Kaplan-Meier method. Results As of April 4, 2016, data were available for 2017 treated pts, of whom 399 (20%) had BL CNS mets, with a median follow-up of 33 months. Table 1 presents demographic and BL characteristics. The incidence of AEs was similar between pts with and without BL CNS mets. Serious AEs (SAEs) occurred in 112 pts with BL CNS mets (28%) vs 311 of 1618 pts without BL CNS mets (19%), and the frequency of SAEs was comparable to that observed in EMILIA. However, nervous system disorder SAEs, such as seizure, epilepsy, and brain edema, occurred more frequently in pts with BL CNS mets (30 pts [8%]) vs 18 pts [1%] with no BL CNS mets. Mean T-DM1 treatment duration was 8.0 months (median 8 cycles; range 1–55) in pts with BL CNS mets and 9.4 months (median 9 cycles; range 1–57) in pts with no BL CNS mets. Median PFS was 5.5 months in pts with BL CNS mets vs 7.9 months in pts with no BL CNS mets. A decrease in the size of brain target lesions was observed during T-DM1 treatment in 84 of 126 pts with measurable CNS lesions. Table 1. BL characteristics CNS mets at BL (n=399)No BL CNS mets (n=1618)Median age, yrs (range)52 (28–83)55 (26–88)ECOG performance status, n (%) 0193 (48)929 (57)1174 (44)605 (37)232 (8)83 (5)Hormone receptor status, n (%) ER and/or PR positive246 (62)992 (61)ER and PR negative149 (37)593 (37)Median time since initial BC diagnosis, yrs (range)4.8 (0–28)5.0 (0–53)Median time since first metastasis, yrs (range)2.4 (0–25)2.6 (0–35)Median number of prior therapies for metastatic BC (range)3 (0–>10)2 (0–>10) Conclusions This subgroup analysis of KAMILLA is the largest reported cohort of pts with CNS mets treated with T-DM1. The overall safety profile of T-DM1 in pts with BL CNS mets was comparable to that of pts without CNS mets. As might be expected in pts with CNS disease, serious neurological AEs occurred more frequently in pts with BL CNS mets vs those without. Response to T-DM1 was seen in the CNS in pts with BL CNS mets, however, median PFS was lower in pts with BL CNS mets vs those without BL CNS mets. Citation Format: Montemurro F, Ellis P, Delaloge S, Wuerstlein R, Anton A, Button P, Lindegger N, Barrios C. Safety and efficacy of trastuzumab emtansine (T-DM1) in 399 patients with central nervous system metastases: Exploratory subgroup analysis from the KAMILLA study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-10.

Hepatitis C: efficacy and safety in real life.

Interferon-free combinations were registered in 2014 and 2015 for the treatment of chronic HCV infection. As a result, real-world experience has been gathered in the last year and this paper presents data available in September 2016. Real-world studies on the efficacy of the ledipasvir/sofosbuvir (LDV/SOF)±ribavirin (RBV) regimen showed a sustained virologic response (SVR) rate of between 91% and 98%. The SVR rate in the 13858 patients included in this paper was 94%, and 92% in the 3506 patients with cirrhosis. In a number of recently published real-world studies evaluating ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±RBV, the SVR rate was between 92% and 100%. The SVR rate of the 4260 patients included in the studies in this paper was 97% and the rate was the same in the 1647 patients with cirrhosis. Recently, data evaluating SOF/simeprevir±RBV showed an SVR rate >90%, while in combination with daclatasvir this rate reached approximately 95%. The safety data available for LDV/SOF±RBV and OBV/PTV/r±DSV±RBV show that discontinuation due to adverse events was necessary in no more than 3% of patients and the frequency of serious adverse events was between 0 and 11%, in particular in real-world studies. Because of the similar efficacy and safety, real-world data support the use of either the LDV/SOF±RBV or OBV/PTV/r±DSV±RBV regimen in patients with genotypes 1 or 4. There is still not enough real-world data in patients with genotype 3 and other genotypes.

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

Background: Sickle cell anemia (SCA) is characterized by significant phenotypic variability. DOVE1 was a Phase 3, double-blind, randomized, parallel-group, placebo-controlled, multinational study that investigated the efficacy and safety of prasugrel, a P2Y12 adenosine diphosphate receptor antagonist, for reduction of vaso-occlusive crises (VOCs), a composite of painful crisis or acute chest syndrome, in 2- to <18-year-olds with SCA (age cohorts: 2 to <6 years, 6 to <12 years, and 12 to <18 years) (NCT01794000).Methods: DOVE was conducted at 51 sites in 13 countries across 4 continents. A total of 341 subjects were randomized (prasugrel, n=171; placebo, n=170) and SCA genotypes (homozygous hemoglobin S; hemoglobin Sβ0 thalassemia) were included. Eligibility required ≥2 VOCs in the prior year. Baseline clinical and laboratory characteristics and study endpoints were compared by region. Since no overall treatment effect was found, data provided reflect the combined 341 subjects (Americas, N=57; sub-Saharan Africa [SSA], N=148; North Africa/Middle East, N=110; Europe, N=26).Results: Per regional enrollment, the largest proportion of subjects were 6 to <12 years in SSA (48.6% [n=72]), 12 to <18 years in the Americas (45.6% [n=26]) and North Africa/Middle East (58.2% [n=64]), but more evenly divided among the 3 age groups in Europe (30.8-34.6% [n=8-9]). Self-reported racial groupings differed by region (p<0.001): 100% white in North Africa/Middle East; 100% black in SSA; 19.2% white, 76.9% black, and 3.8% multiple in Europe; and 1.8% white, 96.4% black, and 1.8% multiple in the Americas. Mean body mass index was <17 in SSA and Europe (15.3 and 16.6 kg/m2) but >18 in North Africa/Middle East and the Americas (18.3 and 18.1 kg/m2) (p<0.001). Mean blood pressures were lowest in SSA (systolic: 99.0 vs. 105.4-108.0 mmHg, p=0.004; diastolic: 58.3 vs. 60.4-62.9 mmHg, p=0.003).The proportion of subjects with history of acute chest syndrome prior to enrollment was lower in SSA (6.1%) than other regions (18.2-66.7%, p<0.001). Mean number of VOCs in the year prior to enrollment was higher in the Americas than other regions (5.8 vs. 3.2-3.4, p=0.041).Hydroxyurea (HU) use at baseline varied by region: 91.2% in the Americas, 72.7% in North Africa/Middle East, 42.3% in Europe, and 6.8% in SSA (p<0.001). For subjects not on HU at baseline (Table 1), mean hemoglobin at baseline was lowest in SSA (7.6 g/dL); reticulocyte count was lowest in the Americas (214.8 billion/L) and highest in Europe (327.8 billion/L) (p=0.004).For all geographic regions, the most frequent serious adverse events (SAEs) were classified as blood and lymphatic system disorders, with the highest percentage reported as painful crisis. The second most frequent SAEs in SSA, North Africa/Middle East, and Europe were various infections and infestations. The second most frequent in the Americas was respiratory, thoracic, and mediastinal disorders; all were reported as acute chest syndrome.The overall rate of VOCs (events per patient-year) was 3.2 in Europe, 3.0 in the Americas, 2.6 in SSA, and 2.0 in North Africa/Middle East. The percentage of patients hospitalized for VOCs was greatest in Europe (76.9%) compared to other regions (28.4-57.9%); however, mean hospital stay per VOC was similar across regions (5.3-6.2 days). The percentage of VOCs causing hospitalization was highest in Europe (67.7%), followed by North Africa/Middle East (48.7%), the Americas (46.5%), and SSA (26.4%). In SSA, the majority of VOCs were managed as outpatient hospital visits (67.9%), whereas other regions more frequently used inpatient hospital visits (33.2-55.2%). Regardless of region, almost all VOCs were treated with analgesics (overall: 99.5%) and approximately half were treated with intravenous (IV) fluids (overall: 54.4%). In contrast, the proportion of VOC-related transfusions was greater in North Africa/Middle East and Europe (18.6% and 18.8%) than in the Americas and SSA (10.0% and 6.4%).Conclusions: In the DOVE study, management of VOCs with analgesics and IV fluids was similar across regions. However, there were regional differences in VOC-related hospitalizations and transfusions that may reflect differences in culture, utilization of resources, disease severity, or a combination of factors.

Five-year Efficacy and Safety of Tocilizumab Monotherapy in Patients with Rheumatoid Arthritis Who Were Methotrexate- and Biologic-naive or Free of Methotrexate for 6 Months: the AMBITION Study.

To report on the 5-year efficacy and safety results of the AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) monotherapy study (ClinicalTrials.gov: NCT00109408, NCT00720798). Patients with rheumatoid arthritis for whom biologics had not failed or who did not discontinue methotrexate because of lack of efficacy or tolerability were followed up for 5 years to assess the efficacy and serious adverse events (SAE) of tocilizumab (TCZ) monotherapy. Longterm efficacy results showed that efficacy was maintained or improved for up to 264 weeks in patients receiving TCZ monotherapy. Serious infection was the most frequent SAE; no new safety signals were reported. Longterm monotherapy with TCZ demonstrated continuing efficacy and safety.

Hemodynamic, management, and outcomes of patients admitted to emergency department with heart failure.

BackgroundHeart failure is one of the leading reasons for hospitalization in developed countries. Our goal was to describe the hemodynamic vital signs (heart rate and systolic blood pressure) of patients presenting to the emergency department (ED) with heart failure and to describe the frequency of adverse events for patients presenting with various heart rate and systolic blood pressure values.MethodWe conducted two prospective cohort studies of heart failure conducted at six Canadian teaching hospital sites and this study was a secondary analysis of these data. The primary outcome was serious adverse events defined as death from any cause within 30 days of the ED visit or any complication following within 14 days of the index ED visit.ResultsWe included a convenience sample of adults > 50 years of age who presented with acute shortness of breath or new-onset heart failure. In total, 1,638 patients were included in this analysis. Patients with heart rates < 50 % MHR (maximal heart rate) and systolic blood pressure (SBP) > 140 mmHg had the lowest rate of serious adverse events (6 %). patients with heart rates > 75 % MHR had the highest rate of serious adverse events, regardless of the SBP. Among patients with heart rates > 75 % MHR, the proportion of serious adverse events decreased as SBP increased (30 % when SBP < 120 mmHg, 24 % when SBP between 120 and 140 mmHg, and 21 % when SBP > 140 mm Hg). Patients with heart rates < 50 % MHR and with SBP > 140 mm Hg had the lowest rate of admissions to hospital (38 %).ConclusionsWe found a relatively high frequency of serious adverse events among patients who present to the ED with heart failure, particularly among the patients having low systolic blood pressure and high heart rate.

Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD.

Bronchodilators are a central component for treating exacerbations of chronic obstructive pulmonary disease (COPD) all over the world. Clinicians often use nebulisers as a mode of delivery, especially in the acute setting, and many patients seem to benefit from them. However, evidence supporting this choice from systematic analysis is sparse, and available data are frequently biased by the inclusion of asthma patients. Therefore, there is little or no formal guidance regarding the mode of delivery, which has led to a wide variation in practice between and within countries and even among doctors in the same hospital. We assessed the available randomised controlled trials (RCTs) to help guide practice in a more uniform way. To compare the effects of nebulisers versus pressurised metered dose inhalers (pMDI) plus spacer or dry powder inhalers (DPI) in bronchodilator therapy for exacerbations of COPD. We searched the Cochrane Airways Group Trial Register and reference lists of articles up to 1 July 2016. RCTs of both parallel and cross-over designs. We included RCTs during COPD exacerbations, whether measured during hospitalisation or in an outpatient setting. We excluded RCTs involving mechanically ventilated patients due to the different condition of both patients and airways in this setting. Two review authors independently assessed studies for inclusion, extracted data and assessed the risk of bias. We report results with 95% confidence intervals (CIs). This review includes eight studies with a total of 250 participants comparing nebuliser versus pMDI plus spacer treatment. We identified no studies comparing DPI with nebulisers. We found two studies assessing the primary outcome of 'change in forced expiratory volume in one second (FEV1) one hour after dosing'. We could not pool these studies, but both showed a non-significant difference in favour of the nebuliser group, with similar frequencies of serious adverse events. For the secondary outcome, 'change in FEV1 closest to one hour after dosing': we found a significant difference of 83 ml (95% CI 10 to 156, P = 0.03) in favour of nebuliser treatment. For the secondary outcome of adverse events, we found a non-significant odds ratio of 1.65 (95% CI 0.42 to 6.48) in favour of the pMDI plus spacer group. There is a lack of evidence in favour of one mode of delivery over another for bronchodilators during exacerbations of COPD. We found no difference between nebulisers versus pMDI plus spacer regarding the primary outcomes of FEV1 at one hour and safety. For the secondary outcome 'change in FEV1 closest to one hour after dosing' during an exacerbation of COPD, we found a greater improvement in FEV1 when treating with nebulisers than with pMDI plus spacers.A limited amount of data are available (eight studies involving 250 participants). These studies were difficult to pool, of low quality and did not provide enough evidence to favour one mode of delivery over another. No data of sufficient quality have been published comparing nebulisers versus DPIs in this setting. More studies are required to assess the optimal mode of delivery during exacerbations of COPD.

Efficacy and safety of boceprevir based triple therapy in Hungarian patients with hepatitis C genotype 1 infection, advanced stage fibrosis and prior treatment failure

During 2011 and 2013, 155 Hungarian hepatitis C genotype 1 infected patients, mostly with advanced liver fibrosis, who did not respond to prior peginterferon + ribavirin dual therapy, started boceprevir based triple therapy in an early access program. Efficacy and safety of the therapy was retrospectively assessed based on sustained virologic responses, as well as on frequency and type of serious adverse events and of those leading to therapy discontinuation. In an intent-to-treat analysis 39.4% patients (61/155) reached sustained virologic response. Amongst pervious relapsers, partial responders and null-responders 59.5%, 41.4 % and 22.9% (p<0.05 compared to the other two categories) reached sustained virologic response, respectively, while amongst non-cirrhotics and cirrhotics 52.5% and 31.3% (p<0.05 compared to the non-cirrhotics) achieved sutained virologic response, respectively. Six out of the 33 most difficult to cure patients (previous null responder and cirrhotic) have reached sustained virologic response (18.2%). Frequency of early discontinuations due to insufficient virologic response was 31.1%, while due to adverse event 10.3%. Reported frequency of serious adverse event was 9.8%. These events represented anemia, diarrhoea, depression, agranulocytosis, elevated aminotransferases, generalized dermatitis and severe gingivitis with loss of teeth, prolonged QT interval on ECG, generalized oedema and severe dyspnoea, uroinfection, exacerbation of Crohn's disease, Campylobacter pylori infection and unacceptable weakness and fatigue. Eight patients received transfusion, 4 patients erythropoietin and 1 granulocyte colony stimulating factor during therapy. No death has been reported. With boceprevir based triple therapy, one of the bests available in 2011-2013 in Hungary, a relevant proportion of hepatitis C infected patients with advanced liver fibrosis achieved sustained viral response. In this cohort, side-effects resembled those reported in registration studies, and resulted in therapy discontinuation with consequent treatment failure in a relevant number of patients. Efficacy and tolerability of boceprevir-based triple therapy are suboptimal, particularly in the most difficult to cure patient population. Orv. Hetil., 2016, 157(34), 1366-1374.

Abstract 3915: PBA2, a dual BCR-ABL and GSK3βkinases inhibitor, represses a wide array of Imatinib resistant cell lines in chronic myeloid leukemia

Abstract Despite the clinical efficacy of the BCR-ABL (Tyrosine Kinase Inhibitors) TKIs for the treatment of Chronic Myeloid Leukemia (CML), BCR-ABL-T315I mutation still confers higher-level resistance to imatinib and the second generation BCR-ABL TKIs. Ponatinib, as the third generation BCR-ABL TKIs, has the potential activity against CML with T315I mutant BCR-ABL whereas high frequency of serious adverse events limits its clinical use. Through a compound library screen, we identified a novel compound PBA2, a dual kinases inhibitor of GSK3β and BCR-ABL, as a promising agent for the treatment of imatinib-resistant CML. Not only can PBA2 inhibit cell growth but also induce terminal cell differentiation in a series of kinase mutant CML cell lines as well as T315I mutation. Remarkably, the mechanism of action of this compound involved the simultaneous inhibition effect of BCR-ABL and GSK3β, which could be a fruitful approach to suppress the β-catenin/CBP signal pathway that promoted the interaction of β-catenin/p300, leading to growth inhibition and subsequent terminal differentiation. More importantly, we found a novel molecular link between CBP and BCR-ABL. We showed that CBP could regulate BCR-ABL expression through activating CREB which binds to the BCR-ABL promoter in CML cells to start transcription, and the BCR-ABL in turns affect the expression level of CBP. This positive feedback pathway between CBP and BCR-ABL represents a novel way for the treatment of CML, and the novel compound PBA2 targeting at this loop deserves further investigation in clinical trial. Citation Format: Ke Yang, li-Wu Fu. PBA2, a dual BCR-ABL and GSK3βkinases inhibitor, represses a wide array of Imatinib resistant cell lines in chronic myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3915.

Antipsychotics for fibromyalgia in adults.

Antipsychotics for fibromyalgia in adults.

Wirksamkeit, Verträglichkeit und Sicherheit von Cannabinoiden bei neuropathischen Schmerzsyndromen

Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2 with nabilone and 1 with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12). Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

Belatacept and Long-Term Outcomes in Kidney Transplantation

BackgroundIn previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study.MethodsWe randomly assigned kidney-transplant recipients to a more-intensive belatacept regimen, a less-intensive belatacept regimen, or a cyclosporine regimen. Efficacy and safety outcomes for all patients who underwent randomization and transplantation were analyzed at year 7 (month 84).ResultsA total of 666 participants were randomly assigned to a study group and underwent transplantation. Of the 660 patients who were treated, 153 of the 219 patients treated with the more-intensive belatacept regimen, 163 of the 226 treated with the less-intensive belatacept regimen, and 131 of the 215 treated with the cyclosporine regimen were followed for the full 84-month period; all available data were used in the analysis. A 43% reduction in the risk of death or graft loss was observed for both the more-intensive and the less-intensive belatacept regimens as compared with the cyclosporine regimen (hazard ratio with the more-intensive regimen, 0.57; 95% confidence interval [CI], 0.35 to 0.95; P=0.02; hazard ratio with the less-intensive regimen, 0.57; 95% CI, 0.35 to 0.94; P=0.02), with equal contributions from the lower rates of death and graft loss. The mean estimated glomerular filtration rate (eGFR) increased over the 7-year period with both belatacept regimens but declined with the cyclosporine regimen. The cumulative frequencies of serious adverse events at month 84 were similar across treatment groups.ConclusionsSeven years after transplantation, patient and graft survival and the mean eGFR were significantly higher with belatacept (both the more-intensive regimen and the less-intensive regimen) than with cyclosporine. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00256750.)

Safety and Clinical Benefit of Lentiviral Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency characterized by thrombocytopenia, recurrent infections, eczema, autoimmunity and increased susceptibility to malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is a recognized curative treatment for WAS, but is still associated with transplant-related complications and long-term morbidity, particularly in the absence of fully matched donors. In April 2010, we initiated a phase I/II clinical trial with hematopoietic stem cell (HSC) gene therapy (GT) for WAS. The investigational medicinal product (IMP) consists of autologous CD34+ HSC engineered with a lentiviral vector (LV) driving the expression of WAS cDNA from an endogenous 1.6 kb human WAS promoter (LV-WAS), infused after a reduced intensity conditioning (RIC) based on anti-CD20 mAb, targeted busulfan and fludarabine. We previously reported early follow up (FU) results from the first 3 patients (Aiuti et al., Science 2013). Seven patients (Zhu score ≥3) have now been treated at a median age of 1.9 years (1.1 - 11.1). As of May 2015, all patients are alive with a median FU of 3.2 years (0.7 - 5.0). CD34+ cell source was bone marrow (BM) (n=5), mobilized peripheral blood (MPB) (n=1) or both (n=1). IMP dose ranged between 7.0 and 14.1 x106 CD34+/kg, containing on average 94.4 ± 3.5% transduced clonogenic progenitors and a mean vector copy number (VCN)/genome in bulk CD34+ cells of 2.7 ± 0.8. No adverse reactions were observed after IMP infusion and RIC was well tolerated. Median duration of severe neutropenia was 19 days; granulocyte-colony stimulating factor was administered to 1 patient.In the first 6 treated patients with FU >2 years, we observed robust and persistent engraftment of gene corrected cells. At the most recent FU, transduced BM progenitors ranged between 20.7 and 59.7%, and LV-transduced cells were detected in multiple lineages, including PB granulocytes (VCN 0.34 - 0.93) and lymphocytes (VCN 1.18 - 2.73). WAS protein expression, measured by flow-cytometry, was detected in the majority of PB platelets [mean ± standard deviation (SD), 71.4 ± 14.0%], monocytes (63.3 ± 18.5%) and lymphocytes (78.9 ± 14.9%). Lymphocyte subset counts were normal in most patients and proliferative response to anti-CD3 mAb was in the normal range in all 6 patients.After immune reconstitution, a marked reduction in the annualized estimated rate of severe infections was observed, as compared with baseline (figure 1A). The first 6 treated patients discontinued anti-infective prophylaxis and no longer require a protected environment. Four patients stopped immunoglobulin supplementation and 2 of them developed specific antibodies after vaccination. Eczema resolved in 4 patients and remains mild in 2. No clinical manifestations of autoimmunity were observed ≥1 year after GT in accordance with improved B-cell development and decreased autoantibody production. All patients became platelet transfusion independent at a median of 4 months after GT (range: 1.0 - 8.7). Mean platelet counts progressively increased after treatment (mean ± SD: before GT, 13.4 ± 7.8 x109/l; 24-30 month FU, 45.8 ± 22.0 x109/l; 36-42 month FU, 57.0 ± 18.7 x109/l).The frequency and the severity of bleeding events decreased after the 1st year of FU. No severe bleedings were recorded after treatment (figure 1B).Quality of life improved in all patients after GT. From the 2nd year of FU, the number of hospitalizations for infections decreased and no hospitalizations due to bleeding were observed after treatment.The seventh patient treated, who received MPB derived CD34+ cells only, showed the fastest platelet recovery with the highest level of transduced myeloid cell engraftment, and is clinically well.No Serious Adverse Events (SAE) related to the IMP were observed. The most frequent SAE were related to infections (85%), occuring mainly during the 1st year of FU.Importantly, no evidence of abnormal clonal proliferations emerged after GT and the LV integration profile show a polyclonal pattern, with no skewing for proto-oncogenes.In conclusion, this updated report in 7 WAS patients show that GT is well tolerated and leads to a sustained clinical benefit. The high level of gene transfer obtained with LV-WAS results in robust engraftment of transduced HSC, even when combined with RIC. Prolonged FU will provide additional information on the long-term safety and clinical efficacy of this treatment. [Display omitted] DisclosuresVilla:Fondazione Telethon: Research Funding. Dott:GlaxoSmithKline: Consultancy. van Rossem:GlaxoSmithKline: Employment. Naldini:Salk Institute: Patents & Royalties: Lentiviral vectors; San Raffaele Telethon Institute: Patents & Royalties: Lentiviral vector technology; GlaxoSmithKline: Other: GSK licensed gene therapies developed at my Institute and the Institute receives milestone payments; Sangamo Biosciences: Research Funding; Biogen: Research Funding; Genenta Sciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Aiuti:GlaxoSmithKline (GSK): Other: PI of clinical trial which is financially sponsored by GSK; Fondazione Telethon: Research Funding.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial

BMS-663068 is an oral prodrug of BMS-626529, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 cells. AI438011 is an ongoing trial investigating the efficacy, safety, and dose-response of BMS-663068 in treatment-experienced, HIV-1-infected patients. Herein we present the results of the primary analysis. AI438011 is a phase 2b, randomised, active-controlled trial, at 53 hospitals and outpatient clinics across ten countries in North and South America, Europe, and Africa. Individuals with an HIV-1 RNA viral load of at least 1000 copies per mL and a BMS-626529 half-maximum inhibitory concentration lower than 100 nmol/L were randomly assigned (1:1:1:1:1) to receive either BMS-663068 at 400 mg twice daily, 800 mg twice daily, 600 mg once daily, or 1200 mg once daily or ritonavir-boosted atazanavir (300 mg of atazanavir and 100 mg of ritonavir once daily), each with 400 mg of raltegravir twice daily and 300 mg of tenofovir disoproxil fumarate once daily as a backbone. The sponsor, participants, and investigators were masked for BMS-663068 dose but not for allocation. Primary endpoints were the proportion of patients with an HIV-1 RNA viral load less than 50 copies per mL (response rate) at week 24 and the frequency of serious adverse events and adverse events leading to discontinuation, up to the week 24 analysis. The primary analyses included all patients who received at least one dose of study drug (modified intention-to-treat population). This study is registered at ClinicalTrials.gov, NCT01384734. Between July 26, 2011, and July 16, 2012, 581 participants were assessed for eligibility. Of these, 254 patients were randomly assigned to receive either BMS-663068 (n=52 for the 400 mg twice daily group, n=50 for the 800 mg twice daily group, n=51 for the 600 mg once daily group, and n=50 for the 1200 mg once daily group) or ritonavir-boosted atazanavir (n=51). 200 patients received at least one dose of BMS-663068, and 51 patients received at least one dose of ritonavir-boosted atazanavir. At week 24, 40 (80%) of 50 patients in the BMS-663068 400 mg twice daily group, 34 (69%) of 49 patients in the 800 mg twice daily group, 39 (76%) of 51 patients in the 600 mg once daily group, and 36 (72%) of 50 patients in the 1200 mg once daily group had an HIV-1 RNA viral load less than 50 copies per mL, compared with 38 (75%) of 51 patients in the ritonavir-boosted atazanavir group. Serious adverse events were noted in 13 (7%) of 200 patients in the BMS-663068 groups and five (10%) of the 51 patients in the ritonavir-boosted atazanavir group. Four (2%) of the 200 patients in the BMS-663068 groups and two (4%) of the 51 patients in the ritonavir-boosted atazanavir group discontinued because of adverse events. No serious adverse events or adverse events leading to discontinuation were BMS-663068-related. Grade 2-4 adverse events related to study drug(s) occurred in 17 (9%) of 200 patients across the BMS-663068 groups and 14 (27%) of 51 patients in the ritonavir-boosted atazanavir group. For the BMS-663068 groups these events were mostly single instances with no dose relation and for the ritonavir-boosted atazanavir group these were mostly gastrointestinal or hepatobiliary disorders associated with hyperbilirubinaemia. In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a phase 3 trial in heavily treatment-experienced individuals. Bristol-Myers Squibb.

Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents.

There are less data on omalizumab treatment in pediatric asthma than in adult population. Thus, to establish the efficacy and safety of subcutaneous omalizumab as an add-on therapy, a systematic review of placebo-controlled studies was performed. Primary outcome was the frequency of asthma exacerbations. Secondary outcomes included spirometric measures, rescue medication use, asthma symptoms, health-related quality of life, and adverse events. Three randomized controlled trials (1381 participants) fulfilled the selection criteria. During the stable phase, omalizumab decreased the number of patients with at least one significant asthma exacerbation (26.7% vs. 40.6%, NNTB = 7, 95% CI, 5, 11). The predefined post hoc subgroup analysis showed that duration of treatment did not influence this result. During the steroid reduction phase, omalizumab reduced the number of patients with at least one exacerbation (RR = 0.48, 95% CI, 0.38, 0.61; NNTB = 6, 95% CI, 4, 8) and also the mean number of asthma exacerbations per patient (MD = -0.44, 95% CI, -0.72, -0.17) when compared to placebo. The frequency of serious adverse events was similar between omalizumab (5.2%) and placebo (5.6%), and there were no evidence of increased risk of hypersensitivity reactions, nor malignant neoplasms. Data indicate that the efficacy of an add-on omalizumab in patients with moderate-to-severe allergic asthma uncontrolled with recommended inhaled steroid treatment is accompanied by an acceptable safety profile.

Final Analysis of the RO-CHOP Phase Ib/II Study: Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma (PTCL)

Background: Romidepsin is a histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 phase II studies with overall response rates of 25-38%(Piekarz, Blood 2011 & Coiffier, J Clin Oncol 2012). Toxicity is mainly hematologic and digestive. We here present the final analysis of a phase Ib/II trial aiming to evaluate the safety, tolerability and efficacy of romidepsin in association with CHOP in patients with previously untreated PTCL.Patients & methods: Patients with PTCL were planned to receive 8 cycles of CHOP(cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1 – 5) in association with varying doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 days 1 & 8 was chosen. The dose-variation scheme followed a traditional “3+3” design. Dose-limiting toxicities (DLT) were considered during the first 2 cycles. DLT was initially defined as: Non hematological toxicity grade 3-4 or hematological toxicity grade 3 lasting more than 7 days or grade 4 lasting more than 3 days. The protocol was subsequently amended to tolerate if lasting less than 10 (grade 3) or 7 days (grade 4).Results: Eighteen patients have been treated in phase Ib of the study (Dupuis, Hematol Oncol 2013). Significant, albeit tolerable hematological toxicity having been observed in the first two cohorts, the definition of DLT was modified during the course of the study. The dose of 12 mg/m2 was chosen as the recommended dose for phase II. Nineteen patients were treated in the phase II part of the study. Two patients had an early cardiac event (myocardial infarction) and were excluded from the efficacy analysis. A third patient had a cardiac event (acute cardiac failure) after cycle 1 day one and continued on CHOP alone. There were no deaths attributable to toxicity. Late hematological toxicity was observed, thus some cycles after cycle 2 were delivered with only one administration of romidepsin at day 1: Among 509 planned romidepsin administrations, 93 (18%) were cancelled on decision of the investigator, mainly during the last 2 cycles and mainly because of hematological toxicity. Sixty-seven percent of patients had at least on serious adverse event (SAE). The most frequent SAEs were: Febrile neutropenia (13.5%), general physical health deterioration (13.5%), lung infection (10.8%), vomiting (8%). Thirty-eight percent of patients had Grade 3-4 neutropenia at any time of the study, 19% grade 3-4 thrombocytopenia, 8% grade 3-4 anemia. Observed response rates (IHP 2007 criteria) were (n=35): Complete response 51%, partial response 17%, and progressive disease 25%. With a median follow-up of 17.5 months, the estimated progression-free survival is 57% at 18 months with 5 progressions among the 24 responding patients. The overall survival rate at 18 months is 76,5%. Longer follow-up will be presented during the meeting.Conclusion: Romidepsin can be combined with CHOP at the price of foreseeable hematological toxicity. Some cardiovascular events have been observed but the relationship with romidepsin is questionable. The progression-free survival rates seem promising, and the combination of romidepsin and CHOP is actually compared with CHOP alone in the setting of a phase III randomized trial (phase III RO-CHOP study).References :1. Piekarz R, Blood. 2011;117(22):5827-34.2. Coiffier B, J Clin Oncol. 2012;30(6):631-63. Dupuis J, Hematological Oncology 2013;31(Suppl.1):96-150 DisclosuresOff Label Use: Romidepsin in association with CHOP for first line treatment of peripheral T-cell lymphoma. Morschhauser:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Tilly:Celgene: Research Funding. Coiffier:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees.

PC-FACS

PC-FACS

A Randomized Trial Comparing Treatments for Varicose Veins

BackgroundUltrasound-guided foam sclerotherapy and endovenous laser ablation are widely used alternatives to surgery for the treatment of varicose veins, but their comparative effectiveness and safety remain uncertain.MethodsIn a randomized trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of foam, laser, and surgical treatments. Primary outcomes at 6 months were disease-specific quality of life and generic quality of life, as measured on several scales. Secondary outcomes included complications and measures of clinical success.ResultsAfter adjustment for baseline scores and other covariates, the mean disease-specific quality of life was slightly worse after treatment with foam than after surgery (P=0.006) but was similar in the laser and surgery groups. There were no significant differences between the surgery group and the foam or the laser group in measures of generic quality of life. The frequency of procedural complications was similar in the foam group (6%) and the surgery group (7%) but was lower in the laser group (1%) than in the surgery group (P<0.001); the frequency of serious adverse events (approximately 3%) was similar among the groups. Measures of clinical success were similar among the groups, but successful ablation of the main trunks of the saphenous vein was less common in the foam group than in the surgery group (P<0.001).ConclusionsQuality-of-life measures were generally similar among the study groups, with the exception of a slightly worse disease-specific quality of life in the foam group than in the surgery group. All treatments had similar clinical efficacy, but complications were less frequent after laser treatment and ablation rates were lower after foam treatment. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN51995477.)

A Randomized Multicentre Phase Ii Study of Pazopanib Plus Best Supportive Care (Bsc) Vs Bsc Alone in Metastatic Gastrointestinal Stromal Tumors (Gist) Resistant to Imatinib and Sunitinib

ABSTRACT Aim: GIST is the most common mesenchymal neoplasm of the gastrointestinal tract. In unresectable and metastatic or locally advanced disease, imatinib followed by sunitinib, then regorafenib represent the standard treatments in 1st, 2nd and 3rd line, respectively. Pazopanib is an active treatment in soft tissue sarcomas; it has never been evaluated in a randomized setting in advanced GIST. Methods: Eligible adult patients (pts) with adequate organ functions were randomly assigned (1:1) to receive P + BSC or BSC alone. Randomization was stratified by number of prior drugs (2 vs > = 3). The primary endpoint was Progression-Free Survival (PFS). 80 pts were planned to detect an improvement in the 4-month PFS rate (PFS-4m) from 15% (BSC alone) to 45% (P + BSC) with 5% two-sided a error and 80% power. Secondary objectives included Best Overall Response (BOR), overall survival and safety Results: From Apr 11 to Dec 13, 81 pts were randomized: 40 to P + BSC and 41 to BSC alone. Median age was 63 y (27-85), 70% were males. The intent-to-treat analysis based on investigator-assessed progression showed a significant improvement in PFS with PFS-4m of 47.7% (95% CI 30.9 to 62.7) for P + BSC vs 19.5% (95% CI 9.2 to 32.7) for BSC (HR: 0.56, 95% CI 0.34 to 0.93; stratified log-rank: p = 0.02). 36/41 pts allocated to BSC arm received P following investigator-assessed progression. BOR assessed by central review showed stable disease in 84.2% vs 70.7% and progressive disease in 15.8% vs 26.8% of pts in P + BSC and BSC arms, respectively. 52.5% of pts receiving P + BSC experienced at least one Serious Adverse Event (SAE) vs 14.6% of pts receiving BSC alone. In P + BSC arm, the more frequent SAE were gastrointestinal disorders (n = 7; 17.5%), deterioration of global health status (n = 6; 15%) and pulmonary embolism (n = 5; 12.5%). Conclusions: P combined to BSC improves PFS in pts with advanced GIST resistant to imatinib and sunitinib. Disclosure: J-Y. Blay: Research funding and honoraria from GSK, Novartis, Roche, Pfizer, Bayer; A. Italiano: Research support and honoraria from GSK; P. Cassier: Honoraria from GSK and Servier Travel reimbursment from Novartis, Roche and Servier Research support from Novartis; I.L. Ray-Coquard: Honoraria and research support from GSK & Roche; O. Mir: has acted as a consultant/speaker for Astra-Zeneca, Bayer, GSK, Novartis, Pfizer, Roche and Servier; A. Belleville, J. Gautier and D. Perol: Research support from GSK; A. Le Cesne: Honoraria & Research support from GSK, Pharmamar, Novartis. All other authors have declared no conflicts of interest.

A 52-week, open-label study evaluating the safety and efficacy of tabalumab, an anti-B-cell-activating factor monoclonal antibody, for rheumatoid arthritis.

IntroductionThe objective of this study was to evaluate the long-term safety and efficacy of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor, in rheumatoid arthritis (RA) patients.MethodsPatients with RA who completed one of two 24-week randomized controlled trials (RCTs) participated in this 52-week, flexible-dose, open-label extension study. Patients in RCT1 received intravenous placebo, 30-mg tabalumab or 80-mg tabalumab every 3 weeks, and patients in RCT2 received subcutaneous placebo or 1-, 3-, 10-, 30-, 60- or 120-mg tabalumab every 4 weeks (Q4W). Regardless of prior treatment, all patients in this study received subcutaneous 60-mg tabalumab Q4W for the first 3 months, then a one-time increase to 120-mg tabalumab Q4W (60-mg/120-mg group) and a one-time decrease to 60-mg tabalumab Q4W per patient was allowed (60-mg/120-mg/60-mg group).ResultsThere were 182 patients enrolled: 60 mg (n = 60), 60/120 mg (n = 121) and 60/120/60 mg (n = 1). Pretabalumab baseline disease activity was generally higher in the 60-mg/120-mg group. There was a higher frequency of serious adverse events and treatment-emergent adverse events, as well as infections and injection-site reactions, in the 60-mg/120-mg group. One death unrelated to the study drug occurred (60-mg/120-mg group). In both groups, total B-cell counts decreased by approximately 40% from the baseline level in the RCT originating study. Both groups demonstrated efficacy through 52 weeks of treatment relative to baseline pretabalumab disease activity based on American College of Rheumatology criteria improvement ≥20%, ≥50% and ≥70%; European League against Rheumatism Responder Index in 28 joints; Disease Activity Score in 28 joints–C-reactive protein; and Health Assessment Questionnaire–Disability Index.ConclusionsWith long-term, open-label tabalumab treatment, no unexpected safety signals were observed, and B-cell reductions were consistent with previous findings. Despite differences in RCT originating studies, both groups demonstrated an efficacy response through the 52-week extension.Trial registrationClinicalTrials.gov Identifier: NCT00837811 (registered 3 February 2009).Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0415-2) contains supplementary material, which is available to authorized users.

OP0045 Efficacy of the Euro-Lupus Nephritis Regimen Combined with Abatacept VS Placebo in A North American Lupus Nephritis Population

BackgroundEfficacy of the Euro-lupus nephritis regimen with low dose intravenous cyclophosphamide (LDCY) followed by AZA maintenance (ELN) has previously been established in predominately Caucasian European lupus nephritis patients. The ELN...