Search

Summary Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

the vascular endothelial growth factor (VEGF) pathway plays a prominent role in the growth and progression of human cancer, including non-small cell lung carcinoma (NSCLC). The key mediators of VEGF signaling are a family of related receptor tyrosine kinases that include VEGFR1, VEGFR2, and VEGFR3. The relative expression levels, activity, and cross-talk among these receptors may contribute to response of NSCLC to anti-angiogenic therapies, and a better systematic, translatable approach to categorizing tumors is needed.We comparatively evaluated immunohistochemical expression of the three VEGFRs in archival primary NSCLC tissues (n=96).VEGFR1 and VEGFR2 were localized both in vessels and tumor cells, while VEGFR3 was only localized in tumor vessels. A set of eight VEGFR staining subclasses were identified: Triple VEGFR positive (n=11, 11.5%), VEGFR1 predominant (n=22, 22.9%), VEGFR2 predominant (n=9, 9.4%), VEGFR3 predominant (n=3, 3.1%), VEGFR1/2 predominant (13, 13.5%), VEGFR1/3 predominant (2, 2.1%), VEGFR2/3 predominant (n=8, 8.3%), and triple VEGFR negative (n=28, 29.2%). An objective categorization based on K-means clustering revealed four clusters, three of which showed high VEGFR2 compared to VEGFR3 (30.7% of cases), cases high in both VEGFR2 and VEGFR3 (18.2%), and cases that were negative/low for both VEGFR2 and VEGFR3 (45.4%). A positive association between VEGFR2 and VEGFR3 was found, however no associations were observed between VEGFR1 and VEGFR2, nor VEGFR1 and VEGFR3.The proposed subclasses of NSCLC are an approach for complementing lines of investigation of anti-angiogenic therapies beginning with systematic characterization of the disease.

Summary Background Concern is continuing about increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) who use inhaled corticosteroids. We aimed to establish the effects of inhaled budesonide on the risk of pneumonia in such patients. Methods We pooled patient data from seven large clinical trials of inhaled budesonide (320–1280 μg/day), with or without formoterol, versus control regimen (placebo or formoterol alone) in patients with stable COPD and at least 6 months of follow-up. The primary analysis compared treatment groups for the risk of pneumonia as an adverse event or serious adverse event during the trial or within 15 days of the trial end. Cox proportional hazards regression was used to analyse the data on an intention-to-treat basis. Data were adjusted for patients' age, sex, smoking status, body-mass index, and postbronchodilator percent of predicted forced expiratory volume in 1 s (FEV 1 ). Findings We analysed data from 7042 patients, of whom 3801 were on inhaled budesonide and 3241 were on control treatment, with 5212 patient-years of exposure to treatment. We recorded no significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs 3% [n=103]; adjusted hazard ratio 1·05, 95% CI 0·81–1·37) or a serious adverse event (1% [n=53] vs 2% [n=50]; 0·92, 0·62–1·35), or for time to pneumonia as an adverse event (log-rank test 0·94) or a serious adverse event (0·61). Increasing age and decreasing percent of predicted FEV 1 were the only two variables that were significantly associated with occurrence of pneumonia as an adverse event or a serious adverse event. Interpretation Budesonide treatment for 12 months does not increase the risk of pneumonia in patients with COPD during that time and therefore is safe for clinical use in such patients. Funding Michael Smith Foundation for Health Research.

Background: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6 . It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. Methods: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV1) over 5 years and baseline FEV1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). Results: In the LHS, three IL6 SNPs were associated with decline in FEV1 (0.023⩽p⩽0.041 in additive models). Among them, the IL6 \_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6 \_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6 _-174G/C, were associated with susceptibility to COPD (0.01⩽p⩽0.04 in additive genetic models). Conclusion: The results suggest that the IL6 _-174G/C SNP is associated with a rapid decline in FEV1 and susceptibility to COPD in smokers.

Interleukin (IL)-10 is a type-2 T-helper cell cytokine with a broad spectrum of anti-inflammatory actions. Inflammation plays an important role in the pathogenesis of chronic obstructive pulmonary disease. It was hypothesised that single nucleotide polymorphisms (SNPs) of the genes encoding IL-10 ( IL10 ) and the α subunit of its receptor ( IL10RA ) are associated with changes in, or value of, forced expiratory volume in one second (FEV 1 ) in smoking-induced chronic obstructive pulmonary disease. In total, eleven SNPs of IL10 and IL10RA were studied in 586 White subjects, selected from continuous smokers followed for 5 yrs in the Lung Health Study, who showed the fastest (n = 280) and slowest (n = 306) decline in FEV 1 . These 11 SNPs were also studied in 1,072 participants exhibiting the lowest (n = 538) and highest (n = 534) baseline FEV 1 at the beginning of the Lung Health Study. No association was found in the primary analyses. Although a subgroup analysis showed that the IL-10 3368A allele was associated with a fast decline in FEV 1 , the association did not pass correction for multiple comparisons. No gene–gene interaction of IL10 with IL10RA was found. There was no association of polymorphisms of the genes encoding interleukin-10 and the α subunit of its receptor with the rate of decline in, or value of, forced expiratory volume in one second in smoking-induced chronic obstructive pulmonary disease.

Rationale: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum. Objectives: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality. Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study. Measurements and Main Results: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort. Conclusions: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Background: Several studies suggest that inhaled and oral corticosteroids repress systemic inflammation in chronic obstructive pulmonary disease (COPD). However, the cytokines that may respond to these medications are unclear. Method: We used data from 41 patients with a history of stable moderate COPD (average age 64 years) who were randomised to inhaled fluticasone (500 μg twice daily from a Diskus inhaler), oral prednisone (30 mg daily) or placebo for 2 weeks. Using a multiplexed array system, different serum cytokines that have been implicated in COPD pathogenesis were measured. Results: We found that compared with placebo, inhaled fluticasone significantly reduced levels of soluble tumour necrosis factor receptor-2 (sTNF-R2) by 24% (95% CI, 7—38%; p = 0.01), monocyte chemoattractant protein-1 by 20% (95% CI, 5—32%; p = 0.01), interferon gamma inducible CXCL10 (IP-10) by 43% (95% CI, 3—66%; p = 0.04), and soluble L-selectin levels by 15% (95% CI, 1—28%; p = 0.04). Compared with placebo, oral prednisone reduced levels of sTNF-R2 by 26% (95% CI, 15—36%; p < 0.001), L-selectin by 22% (95% CI, 8—34%; p = 0.004), intercellular adhesion molecule-1 by 31% (95% CI, 9—48%; p = 0.01), pulmonary and activation-regulated chemokine (PARC) by 18% (95% CI, 2—32%; p = 0.03) and IP-10 by 40% (95% CI, 0—64%; p = 0.05). sTNF-R2, L-selectin and IP-10 were significantly reduced by both oral and inhaled corticosteroids. The other cytokines were not significantly repressed by either oral or inhaled corticosteroids. Conclusions: In summary, inhaled and oral corticosteroids significantly repressed a selected number of systemic cytokines in patients with stable, moderate COPD; most of the steroid-responsive cytokines appear to be chemoattractants.

The balance between inflammatory and repair processes is important in maintaining lung homeostasis in chronic obstructive pulmonary disease (COPD). The aim of the present study was to determine whether or not an integrated index of a biomarker involved in inflammation, C-reactive protein (CRP), and another involved in wound repair, fibronectin, may be a good measure to predict clinical outcomes in COPD. Circulating blood levels of CRP and fibronectin were measured in 4,787 individuals with mild-to-moderate COPD who were prospectively followed for7 yrs after blood collection as part of the Lung Health Study. To assess the balance between repair and inflammation, a simple ratio was calculated by dividing fibronectin levels by CRP levels and a Cox proportional hazards model was used to determine the relationship between this ratio and all-cause and disease-specific causes of mortality. The relationship between the fibronectin to CRP ratio and all-cause mortality was L-shaped. There was an exponential decay in the adjusted hazard function (i.e. the risk of mortality) as the ratio decreased until a value of 148 was reached, beyond which point the hazard function did not change significantly. Similar results were observed for the risk of coronary and cardiovascular mortality. Circulating fibronectin to CRP ratio is significantly associated with all-cause mortality of COPD patients. However, in contrast to other biomarkers, the relationship appears to be L-shaped (and not linear), suggesting a threshold at approximately 150. While promising, future studies are needed to validate this simple index as a biomarker in COPD.

Epidemiologic and animal studies have shown that exposure to particulate matter air pollution (PM) is a risk factor for the development of atherosclerosis. Whether PM-induced lung and systemic inflammation is involved in this process is not clear. We hypothesized that PM exposure causes lung and systemic inflammation, which in turn leads to vascular endothelial dysfunction, a key step in the initiation and progression of atherosclerosis. New Zealand White rabbits were exposed for 5 days (acute, total dose 8 mg) and 4 wk (chronic, total dose 16 mg) to either PM smaller than 10 μm (PM10) or saline intratracheally. Lung inflammation was quantified by morphometry; systemic inflammation was assessed by white blood cell and platelet counts and serum interleukin (IL)-6, nitric oxide, and endothelin levels. Endothelial dysfunction was assessed by vascular response to acetylcholine (ACh) and sodium nitroprusside (SNP). PM10 exposure increased lung macrophages ( P < 0.02), macrophages containing particles ( P < 0.001), and activated macrophages ( P < 0.006). PM10 increased serum IL-6 levels in the first 2 wk of exposure ( P < 0.05) but not in weeks 3 or 4. PM10 exposure reduced ACh-related relaxation of the carotid artery with both acute and chronic exposure, with no effect on SNP-induced vasodilatation. Serum IL-6 levels correlated with macrophages containing particles ( P = 0.043) and ACh-induced vasodilatation ( P = 0.014 at week 1, P = 0.021 at week 2). Exposure to PM10 caused lung and systemic inflammation that were both associated with vascular endothelial dysfunction. This suggests that PM-induced lung and systemic inflammatory responses contribute to the adverse vascular events associated with exposure to air pollution.

Background: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV1.Methods: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV1 decline in COPD patients, and whether this relationship is modified by gender and smoking.Results: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV1 of 2.42 +/- 0.19% compared with placebo (p Conclusions: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV1 among those who completed these randomized clinical trials.