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Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.

Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia. ELEVATE TN is a global, phase 3, multicentre, open-label study in patients with treatment-naive chronic lymphocytic leukaemia done at 142 academic and community hospitals in 18 countries. Eligible patients had untreated chronic lymphocytic leukaemia and were aged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30-69 mL/min (calculated by use of the Cockcroft-Gault equation) or Cumulative Illness Rating Scale for Geriatrics score greater than 6. Additional criteria included an Eastern Cooperative Oncology Group performance status score of 2 or less and adequate haematologic, hepatic, and renal function. Patients with significant cardiovascular disease were excluded, and concomitant treatment with warfarin or equivalent vitamin K antagonists was prohibited. Patients were randomly assigned (1:1:1) centrally via an interactive voice or web response system to receive acalabrutinib and obinutuzumab, acalabrutinib monotherapy, or obinutuzumab and oral chlorambucil. Treatments were administered in 28-day cycles. To reduce infusion-related reactions, acalabrutinib was administered for one cycle before obinutuzumab administration. Oral acalabrutinib was administered (100 mg) twice a day until progressive disease or unacceptable toxic effects occurred. In the acalabrutinib-obinutuzumab group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2 and on day 1 (1000 mg) of cycles 3-7. In the obinutuzumab-chlorambucil group, intravenous obinutuzumab was given on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 1 and on day 1 (1000 mg) of cycles 2-6. Oral chlorambucil was given (0·5 mg/kg) on days 1 and 15 of each cycle, for six cycles. The primary endpoint was progression-free survival between the two combination-therapy groups, assessed by independent review committee. Crossover to acalabrutinib was allowed in patients who progressed on obinutuzumab-chlorambucil. Safety was assessed in all patients who received at least one dose of treatment. Enrolment for this trial is complete, and the study is registered at ClinicalTrials.gov, NCT02475681. Between Sept 14, 2015, and Feb 8, 2017, we recruited 675 patients for assessment. 140 patients did not meet eligibility criteria, and 535 patients were randomly assigned to treatment. 179 patients were assigned to receive acalabrutinib-obinutuzumab, 179 patients were assigned to receive acalabrutinib monotherapy, and 177 patients were assigned to receive obinutuzumab-chlorambucil. At median follow-up of 28·3 months (IQR 25·6-33·1), median progression-free survival was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil (median not reached with acalabrutinib and obinutuzumab vs 22·6 months with obinutuzumab, hazard ratio [HR] 0·1; 95% CI 0·06-0·17, p<0·0001; and not reached with acalabrutinib monotherapy vs 22·6 months with obinutuzumab, 0·20; 0·13-0·3, p<0·0001). Estimated progression-free survival at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87-96%), 87% with acalabrutinib monotherapy (81-92%), and 47% with obinutuzumab-chlorambucil (39-55%). The most common grade 3 or higher adverse event across groups was neutropenia (53 [30%] of 178 patients in the acalabrutinib-obinutuzumab group, 17 [9%] of 179 patients in the acalabrutinib group, and 70 [41%] of 169 patients in the obinutuzumab-chlorambucil group). All-grade infusion reactions were less frequent with acalabrutinib-obinutuzumab (24 [13%] of 178 patients) than obinutuzumab-chlorambucil (67 [40%] of 169 patients). Grade 3 or higher infections occurred in 37 (21%) patients given acalabrutinib-obinutuzumab, 25 (14%) patients given acalabrutinib monotherapy, and 14 (8%) patients given obinutuzumab-chlorambucil. Deaths occurred in eight (4%) patients given acalabrutinib-obinutuzumab, 12 (7%) patients given acalabrutinib, and 15 (9%) patients given obinutuzumab-chlorambucil. Acalabrutinib with or without obinutuzumab significantly improved progression-free survival over obinutuzumab-chlorambucil chemoimmunotherapy, providing a chemotherapy-free treatment option with an acceptable side-effect profile that was consistent with previous studies. These data support the use of acalabrutinib in combination with obinutuzumab or alone as a new treatment option for patients with treatment-naive symptomatic chronic lymphocytic leukaemia. Acerta Pharma, a member of the AstraZeneca Group, and R35 CA198183 (to JCB).

Oral use of the selective FLT3 kinase inhibitor gilteritinib in patients who had relapsed or refractory acute myeloid leukemia with FLT3 mutations led to a median overall survival of 9.3 months (vs. 5.6 months with standard chemotherapy) and complete remission with full or partial hematologic recovery in 34.0% of patients (vs. 15.3%).

Among over 1100 patients with pulmonary arterial hypertension who received selexipag, an oral selective IP prostacyclin-receptor agonist, or placebo, the risk of the composite end point of death or complication was lower with selexipag than with placebo at 1.3 years of follow-up. Pulmonary arterial hypertension is a severe disease with a poor prognosis despite available treatment options. 1 Current recommendations support the use of a combination of therapies that target the endothelin, nitric-oxide, and prostacyclin pathways. 2 , 3 Despite the benefits of intravenous prostacyclin therapy, 2 , 4 many patients with pulmonary arterial hypertension die without ever receiving this treatment. 5 , 6 The burden and risks related to the administration of prostacyclin therapy are probably contributing factors. 7 Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin. 8 – 11 In a placebo-controlled, phase 2 trial involving patients who were already receiving treatment for pulmonary . . .

MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6–12) than in the sunitinib group (5·6 months, 3–7; hazard ratio for progression or death 0·60, 0·37–0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. National Institutes of Health and National Cancer Institute.

The addition of sitagliptin to usual care in patients with type 2 diabetes and cardiovascular disease was not associated with any change in the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. Good glycemic control among patients with type 2 diabetes reduces the risk of diabetes-related microvascular complications. 1 – 3 Many antihyperglycemic agents are licensed for the treatment of type 2 diabetes, but questions regarding the long-term cardiovascular safety of some of these agents have been raised. 4 , 5 International regulatory agencies have responded by requiring that new antihyperglycemic agents not only show glucose-lowering ability but also are not associated with clinically meaningful increases in rates of major adverse cardiovascular events. 6 , 7 Sitagliptin, an orally administered dipeptidyl peptidase 4 (DPP-4) inhibitor, prolongs the action of incretin hormones, including glucagon-like peptide 1 and glucose-dependent insulinotropic . . .

Abstract Background A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in preclinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza. Methods Data from 2 separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes included rate of clinical improvement (defined as a decrease of 2 categories on a 7-category ordinal scale) and viral RNA detectability over time. Subhazard ratios (sHRs) were estimated by the Fine and Gray model for competing risks. Results In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on day 14 in the combination group was higher than in the monotherapy group (62.5% vs 42.2%; P = .0247). The adjusted sHR for combination therapy was 2.06 (95% confidence interval, 1.30–3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than the oseltamivir group (67.5% vs 21.9%; P < .01). No significant differences were observed in mortality or other outcomes. Conclusions Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial. No data are available on the clinical effectiveness of favipiravir and oseltamivir combination therapy in influenza. Comparing clinical outcomes between the combination therapy cohort (n = 40) and oseltamivir monotherapy cohort (n = 128), combination therapy may accelerate clinical recovery in critically ill patients.

Among previously untreated patients with chronic lymphocytic leukemia, 3-year progression-free survival was 76.5% with acalabrutinib–venetoclax, 83.1% with acalabrutinib–venetoclax–obinutuzumab, and 66.5% with chemoimmunotherapy.

Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256–507] vs 356 days [249–556]; hazard ratio 0·94 [95% CI 0·61–1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. Astellas.

The substitution of bortezomib for vincristine in R-CHOP resulted in higher rates of complete response and nearly a doubling in progression-free survival among patients with advanced mantle-cell lymphoma not eligible for stem-cell transplantation. Mantle-cell lymphoma is an incurable, aggressive hematologic cancer with a poor prognosis (median survival, 4 to 5 years). 1 , 2 It comprises 5 to 6% of all non-Hodgkin's lymphomas, including approximately 5000 cases per year in the United States. 3 For previously untreated patients who are either ineligible or not considered for intensive chemotherapy and stem-cell transplantation, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard of care 4 – 6 and produces complete response rates of up to 48%. However, progression-free survival is limited (median, 16.6 months). 7 The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma in . . .