Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. METHODS: For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. FINDINGS: 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). INTERPRETATION: Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. FUNDING: Amgen.

Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer.

PURPOSE: To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. RESULTS: One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. CONCLUSION: AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

Case verification of children with asthma in Ontario.

Asthma is an important chronic childhood illness. A population-based surveillance program could measure the burden of illness, but first, the validity of an administrative diagnosis of asthma must be confirmed. The objective was to evaluate the accuracy of population-based outpatient administrative data in identifying children with asthma for the purpose of on-going asthma surveillance and research. Twenty-one primary care physician (PCP) clinics in Ontario participated. Patients under 18 yr old were categorized into three diagnosis categories according to administrative data diagnosis codes: asthma, asthma-related, and non-asthma. In each PCP clinic, for each diagnosis category, 10 charts were randomly selected for abstraction. A panel of experts (blind to the code) reviewed the abstracted charts and identified them as asthma or non-asthma. The reviewers' diagnosis was considered the gold standard. The accuracy of the administrative data diagnosis coding was analyzed using the concepts of diagnostic test evaluation. Six hundred and thirty patient charts were abstracted and reviewed. Overall agreement between the diagnosis provided by expert chart review and the administrative data diagnosis code was 84.8% (p < 0.001), and was 60.2%, 94.8% and 99.5% for the asthma, asthma-related, and non-asthma categories, respectively. Additionally, the sensitivity and specificity were 91.4% and 82.9%, respectively. Agreement between the administrative data diagnosis code and the PCP chart diagnosis was 99.4% (p < 0.001). An administrative data diagnosis code of asthma is sensitive and specific for identifying asthma. By using the results of this study as a starting point, future research will create a cohort of children with asthma to be used for population-based surveillance and research.

What factors are associated with poor developmental attainment in young Canadian children?

BACKGROUND: This study was undertaken to determine the association between poor developmental attainment (PDA) and biological, home environment and socio-demographic factors in a population-based sample of Canadian children. METHODS: Cross-sectional data from two cycles (1994/95 and 1996/97) of the National Longitudinal Survey of Children and Youth were used. Children aged 1-5 years were included. PDA was defined as < or = 15th percentile for motor and social developmental skills (1-3 year olds) or Peabody Picture Vocabulary Test (4-5 year olds). Multiple logistic regression was used. RESULTS: The proportion of children with PDA varies across Canada, between males and females, and by age. Among 1 year olds in Cycle I, having a low birthweight (OR=3.3; 95% CI: 2.1-5.2), being male (OR=1.6; 95% CI: 1.2-2.2) and having a mother who is an immigrant (OR=1.6; 95% CI: 1.1-2.2) increased the odds of PDA. Similar results were observed in Cycle II. Among children aged 4-5 years in Cycle II, having a mother who is an immigrant (OR=5.3; 95% CI: 4.1-6.9) and a mother with low educational attainment (OR=2.8; 95% CI: 2.1-3.9) increased the odds of PDA. Low income was a significant predictor of PDA across all age groups. INTERPRETATION: The strong and consistent associations with living in a low-income household, having a mother with low educational attainment or a mother who is an immigrant highlight the need for targeting developmental assessments and services to this population.

Risk markers for poor developmental attainment in young children: results from a longitudinal national survey.

OBJECTIVE: To evaluate social and environmental determinants of poor developmental attainment among preschool children by means of longitudinal data from a population-based sample of Canadian children. DESIGN: Secondary analysis of data from cycles 1 (1994-1995) and 2 (1996-1997) of the National Longitudinal Survey of Children and Youth using a cohort design with 2-year follow-up. PARTICIPANTS: A total of 4987 children aged 1 to 5 years at baseline, whose biological mother completed risk factor information and who were included in both cycles. MAIN OUTCOME MEASURES: Poor developmental attainment (developing unusually slowly) was defined as scores more than 1 SD below the age-standardized mean for the Motor and Social Development Scale, revised Peabody Picture Vocabulary Test, or Canadian Achievement Tests in mathematics and reading/comprehension, depending on the child's age. RESULTS: The prevalence of sustained poor developmental attainment after 2 years of follow-up was 4.6%. Factors found to be associated with poor developmental attainment included male sex (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.10-1.70), maternal depression (OR, 1.64; 95% CI, 1.25-2.15), low maternal education (OR, 1.57; 95% CI, 1.19-2.08), maternal immigrant status (OR, 1.93; 95% CI, 1.38-2.71), and household low income adequacy (OR, 1.43; 95% CI, 1.11-1.83). CONCLUSIONS: Having a mother who has symptoms of depression, has low education, or is an immigrant, and living in a household with low income adequacy increase the risk of poor developmental attainment in children aged 1 to 5 years. The notable risks associated with these factors indicate them as possible targets for screening and interventions to prevent poor developmental attainment.

Is obesity associated with asthma in young children?

OBJECTIVE: The aim of this study was to evaluate the association between obesity and asthma in a population-based sample of Canadian children. STUDY DESIGN: Baseline data from the National Longitudinal Survey of Children and Youth were used in this cross-sectional study. We included 11199 children age 4 to 11 years whose biological mother reported data on asthma, height, and weight. Body mass index was categorized, and obesity was defined as body mass index >or=85th percentile. Children with asthma had parents who reported the diagnosis, and they took prescribed inhalants, had wheezing or an attack in the previous year, or had their activities limited by asthma. Multiple logistic regression was used. RESULTS: The prevalence of asthma was 9.9%. Maternal history of asthma was a risk factor for asthma among all children. Single child status and maternal depression were risk factors for girls. The odds ratio for asthma, comparing highest and lowest body mass index categories, was 1.02 (99% confidence interval, 0.70-1.46) for boys and 1.06 (99% confidence interval, 0.67-1.69) for girls. CONCLUSION: This study suggests that there is no statistical association between obesity and asthma among Canadian children age 4 to 11 years.