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The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1–17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 109 per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12–17 years, 6–11 years, and 1–5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1–5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6–17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1–5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 109 per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 109 per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3–140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12–17 years, 42% vs 0% for patients aged 6–11 years, and 36% vs 0% for patients aged 1–5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1–4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2–4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 109 per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events. GlaxoSmithKline.

Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia. Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5–15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358. Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1·89 kg (95% CI 0·84 to 2·95) compared with a decrease of a least-squares mean of −0·20 kg (−1·23 to 0·83) for 36 patients in the placebo group (difference 2·09 kg [0·94–3·25]; p=0·0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3–4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each). Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting. Helsinn Therapeutics (US), Helsinn Healthcare SA.

This trial tested the efficacy of eltrombopag, a small nonpeptide agonist of the thrombopoietin receptor, in patients with immune thrombocytopenia who had not had a response to at least one previous treatment for the disorder. At a dose of 50 or 75 mg, the agonist, which had been shown to increase platelet production in normal volunteers, increased platelet counts to a clinically safe level (≥50,000 per cubic millimeter) in most patients. Eltrombopag, a small nonpeptide agonist of the thrombopoietin receptor, increased platelet counts to a clinically safe level (≥5;50,000 per cubic millimeter) in most patients. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which antiplatelet antibodies accelerate the destruction of platelets. In addition, platelet production can be impaired 1 because the antiplatelet antibodies can also damage megakaryocytes. 2 – 4 Although the thrombocytopenia of ITP can be severe, signs of bleeding are usually only minor. Persistently low platelet counts (<20,000 per cubic millimeter), however, are associated with an increased risk of serious bleeding, such as intracranial hemorrhage. 5 , 6 The goal of managing chronic ITP is to maintain platelet counts, with the least possible intervention, at levels that prevent bleeding, thereby reducing treatment-related toxicity. 7 Glucocorticoids and intravenous immunoglobulins . . .

Purpose Cancer cachexia is characterized by decreased body weight (mainly lean body mass [LBM]) and negatively impacts quality of life (QOL) and prognosis. Anamorelin (ONO-7643) is a novel selective ghrelin receptor agonist under development for treating cancer cachexia. Methods In this double-blind, exploratory phase 2 trial, we examined the efficacy and safety of anamorelin in Japanese patients ( n  = 181) with non-small cell lung cancer (NSCLC) and cancer cachexia (≥5 % weight loss within the previous 6 months). The participants were randomized into three groups and were administered 50 or 100 mg anamorelin, or placebo, orally every day for 12 weeks. The co-primary endpoints were the changes from baseline over 12 weeks in LBM and handgrip strength (HGS). Secondary endpoints included body weight, QOL, Karnofsky Performance Scale (KPS), and serum biomarkers. Results The change in LBM over 12 weeks was 0.55 and 1.15 kg in the placebo and 100-mg anamorelin groups, respectively, but the efficacy of anamorelin in HGS was not detected. The changes in body weight were −0.93, 0.54, and 1.77 kg in the placebo, 50-mg anamorelin, and 100-mg anamorelin groups, respectively. Anamorelin (100 mg) significantly improved KPS and QOL-ACD compared with placebo. Administration of anamorelin for 12 weeks was well tolerated. Conclusions This phase 2 study showed that 100 mg anamorelin has promising results in improving lean body mass, performance status, and especially, QOL in patients with cancer cachexia.

In this trial involving patients with cirrhosis and thrombocytopenia, treatment with eltrombopag before invasive procedures reduced the need for platelet transfusions. More thrombotic events of the portal venous system were observed with eltrombopag than with placebo. Thrombocytopenia is frequently observed in patients with chronic liver disease, with studies suggesting that it occurs in up to 76% of patients with cirrhosis. 1 – 3 The degree of thrombocytopenia is proportional to the severity of the liver disease. 4 , 5 Thrombocytopenia increases the risk of bleeding during and after invasive procedures and may result in the cancellation or postponement of elective procedures. 6 Platelet transfusions are commonly used to reduce the risk of bleeding during a procedure, but their short duration of efficacy and the risk of transfusion reactions limit their use. 7 , 8 Furthermore, the development of antiplatelet antibodies (alloimmunization) can cause . . .

Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period. We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30 000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤15 000 per μL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50 000–400 000 per μL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331. Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59–18·73; p<0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients ( vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag. Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment. GlaxoSmithKline.

Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg. In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per μL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per μL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per μL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739. 73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts ≥50 000 per μL; odds ratio [OR] 9·61 [95% CI 3·31–27·86]; p<0·0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0·49 [95% CI 0·26–0·89]; p=0·021). The frequency of grade 3–4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups. Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP. GlaxoSmithKline.

Eltrombopag, an orally active agonist of the thrombopoietin receptor, elevates platelet counts in normal subjects and in patients with immune thrombocytopenia (see the article by Bussell et al. in this issue of the Journal ). This preliminary trial tested the drug in patients with thrombocytopenia and cirrhosis associated with the hepatitis C virus. Eltrombopag was effective in raising the platelet count, thereby allowing for antiviral treatment for up to 12 weeks. Eltrombopag is an orally active agonist of the thrombopoietin receptor. This trial tested the drug in patients with thrombocytopenia and cirrhosis associated with the hepatitis C virus. Eltrombopag was effective in raising the platelet count, thereby allowing for antiviral treatment. Thrombocytopenia is a frequent complication of chronic liver disease and is considered an indicator of advanced disease. 1 – 3 The low platelet count is due partly to the effects of portal hypertension and hypersplenism, 4 decreased thrombopoietin production, 2 , 5 , 6 and virus-induced bone marrow suppression. 7 , 8 Patients with chronic liver disease due to infection with the hepatitis C virus (HCV) who have thrombocytopenia (<75,000 platelets per cubic millimeter) have been routinely excluded from clinical trials of interferon and ribavirin, and few published reports have described the treatment of chronic HCV infection in patients with platelet counts of less than 50,000 per cubic . . .

While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.

BackgroundPatients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and individualized treatment that could impact patient outcomes. In an exploratory analysis of the phase III ENGOT-EN5/GOG-3055/SIENDO study of selinexor maintenance monotherapy 80 mg in advanced/recurrent endometrial cancer, a pre-specified subgroup of patients with TP53 wild type (wt) endometrial cancer showed preliminary activity at long-term follow-up with a generally manageable safety profile (median progression-free survival 27.4 months vs 5.2 months placebo, HR=0.41).Primary ObjectiveTo evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer.Study HypothesisSelinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with TP53wt advanced/recurrent endometrial cancer after systemic therapy versus placebo.Trial DesignThis is a prospective, multicenter, double-blind, placebo-controlled, randomized phase III study designed to evaluate the efficacy and safety of selinexor as a maintenance therapy in patients with advanced or recurrent TP53wt endometrial cancer.Major Inclusion/Exclusion CriteriaEligible patients must have histologically confirmed endometrial cancer, TP53wt confirmed by next-generation sequencing, completed at least 12 weeks of platinum-based therapy with or without immunotherapy, with confirmed partial response or complete response, and primary Stage IV disease or at first relapse.Primary EndpointThe primary endpoint is investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat population.Sample SizeA total of 220 patients will be enrolled.Estimated Dates for Completing Accrual and Presenting ResultsAccrual is expected to be completed in 2024 with presentation of results in 2025.Trial RegistrationNCT05611931