Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent

Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first‑line treatment of ER+/HER2− advanced breast cancer (PALOMA‑1, TRIO‑18)

Purpose Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole signifcantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748; P=0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the fnal overall survival (OS) and updated safety results. Methods Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety. Results A total of 165 patients were randomized. At the data cutof date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratifed hazard ratio for OS was 0.897 (95% CI 0.623–1.294; P=0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to frst subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%). Conclusions Palbociclib plus letrozole treatment led to a numerical but not statistically signifcant improvement in median OS. Pfzer Inc (NCT00721409

J Womens Health (Larchmt)

BackgroundIdentifying and treating chronic diseases, their precursors, and other cardiovascular disease (CVD) risk factors during family planning visits may improve long-term health and reproductive outcomes among low-income women. A cross-sectional study design was used to describe the prevalence of chronic diseases (hypertension, high cholesterol, and diabetes), their precursors (pre-hypertension, borderline high cholesterol, and pre-diabetes), and related CVD risk factors (such as obesity, smoking, and physical inactivity) among low-income women of reproductive age.MethodsPrevalence of chronic diseases, their precursors, and related CVD risk factors were assessed for 462 out of 859 (53.8%) female family planning patients, ages 18\u201344 years, who attended a Title X clinic in eastern North Carolina during 2011 and 2012 and consented to participate. Data were obtained from clinical measurements, blood test results, and questionnaire. Differences in distribution of demographic and health care characteristics and CVD risk factors by presence of prehypertension and pre-diabetes were assessed by Pearson chi-square tests.ResultsThe prevalence of hypertension was 12%, high cholesterol 16%, and diabetes 3%. Nearly two-thirds of women with hypertension were newly diagnosed (62%) as were 75% of women with diabetes. The prevalence of pre-hypertension was 35%, pre-diabetes 31%, obesity 41%, smoking 32%, and physical inactivity 42%. The majority of participants (87%) had one or more chronic disease or related cardiovascular disease risk factor.ConclusionsCVD screening during family planning visits can identify significant numbers of women at risk for poor pregnancy outcomes and future chronic disease and can provide prevention opportunities if effective interventions are available and acceptable to this population.20132015-04-06T00:00:00ZCC999999/Intramural CDC HHS/United States5U48DP001944/DP/NCCDPHP CDC HHS/United States23531099PMC4386647673

Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer

Purpose Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. Patients and methods PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients’ tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. Results: 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. Conclusion: The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports. Trial registration number Phase 2 trial (NCT00932451); Results

TIME DEPENDENT ALTERATIONS IN CENTRAL NERVOUS SYSTEM DOPAMINE RECEPTORS INDUCED BY DOPAMINE AGONIST TREATMENT

Levodopa, the precursor of dopamine, is currently the drug of choice in the treatment of Parkinson\u27s disease. Recently, two direct dopamine agonists, bromocriptine and pergolide, have been tested for the treatment of Parkinson\u27s disease because of reduced side effects compared to levodopa. Few studies have evaluated the effects of long-term treatment of dopamine agonists on dopamine receptor regulation in the central nervous system. Thus, the purpose of this study was to determine whether chronic dopamine agonist treatment produces a down-regulation of striatal dopamine receptor function and to compare the results of the two classes of dopaminergic drugs. Levodopa with carbidopa, a peripheral decarboxylase inhibitor, was administered orally to rats whereas bromocriptine and pergolide were injected intraperitoneally once daily. Several neurochemical parameters were examined from 1 to 28 days. Levodopa minimally decreased striatal D-1 receptor activity but increased the number of striatal D-2 binding sites. Levodopa increased the V(,max) of tyrosine hydroxylase (TH) in all brain regions tested. Protein blot analysis of striatal TH indicated a significant increase in the amount of TH present. Dopamine-beta-hydroxylase (DBH) activity was markedly decreased in all brain regions studied and mixing experiments of control and drug-treated cortices did not show the presence of an increased level of endogenous inhibitors. Bromocriptine treatment decreased the number of D-2 binding sites. Striatal TH activity was decreased and protein blot analysis indicated no change in TH quantity. The specificity of bromocriptine for striatal TH suggested that bromocriptine preferentially interacts with dopamine autoreceptors. Combination levodopa-bromocriptine was administered for 12 days. There was a decrease in both D-1 receptor activity and D-2 binding sites, and a decrease in brain HVA levels suggesting a postsynaptic receptor action. Pergolide produced identical results to the combination levodopa-bromocriptine studies. In conclusion, combination levodopa-bromocriptine and pergolide treatments exhibited the expected down-regulation of dopamine receptor activity. In contrast, levodopa appeared to up-regulate dopamine receptor activity. Thus, these data may help to explain, on a biochemical basis, the decrease in the levodopa-induced side effects noted with combination levodopa-bromocriptine or pergolide therapies in the treatment of Parkinson\u27s disease