text:
Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib.
Ilorasertib monotherapy was administered at 10–180 mg orally once daily (Arm I, n = 23), 40–340 mg orally twice daily (Arm II, n = 28), or 8–32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle.
Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses.
In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue.
Clinical Trial Registration: NCT01110486
Since 2001, at least 27 small-molecule kinase inhibitors have been approved by the US Food and Drug Administration for indications in oncology.1,2 However, because of the multiplicity of targets of most kinase inhibitors, their development and safe clinical use continue to present challenges. Increasingly, cancer therapeutic development plans have incorporated concepts of the pharmacologic audit trail, a systematic serial assessment of an anticancer compound’s pharmacology as it proceeds from preclinical through clinical development.3 Updated methodologic practices4 include a more complete evaluation of pharmacokinetics and systemic pharmacodynamics in human subjects to match the intensive assessment of pharmacodynamics in tumours and tumour models. Especially for kinase inhibitors, these assessments can redirect development of individual compounds, and sharing the results can inform development of other compounds with similar targets.
Commonly, kinase inhibitors are adenosine triphosphate (ATP) mimetics chosen through in vitro assays because of their properties of relative selectivity for a specific intended set of target kinases. Multiple methods have been developed to characterise properties of these compounds in cells and to predict the effects of these drugs on tissues, patients, and populations. For example, high-throughput screening of compound libraries against large numbers of human kinases followed by comprehensive analysis of interaction patterns has provided valuable information about the selectivity of kinase inhibitors.5,6,7 In addition, computational large-scale integration of disease gene expression signatures with compound effect signatures may be a useful strategy to predict compound–disease relationships.8 Integrative computational approaches can also be used to predict the effect of drugs on immune function and minimise side effects.9 Nevertheless, activity predictions, while useful, are approximations, and multiple factors determine how these agents will affect patients. It therefore becomes important to re-characterise these drugs during the conduct of first-in-human and other early phase trials. A change in a compound’s development plan and design of subsequent studies should be based on this initial in-human re-characterisation.
Ilorasertib (ABT-348) is an ATP-mimetic kinase inhibitor that was selected for clinical development on the basis of its dual-inhibition properties of Aurora and vascular endothelial growth factor receptor (VEGFR) kinase signalling pathways.10 Aurora kinases are key regulators of mitosis that are overexpressed in many cancer types and have been identified as candidate drug targets for cancer therapy.11,12,13 In enzyme assays to determine kinase inhibitory activity, ilorasertib showed in vitro potency against a panel of cancer-related kinases (Table 1,10,14 with greater potency for inhibiting binding and cellular autophosphorylation of Aurora B and C, compared with Aurora A. In addition, ilorasertib inhibited VEGFR and platelet-derived growth factor receptor (PDGFR) families of kinases in the low nanomolar range. As with inhibition of Aurora kinase activity, inhibition of VEGFR/PDGFR kinases in biochemical assays correlated with inhibition of cellular autophosphorylation of targeted kinases for VEGFR2, fms-like tyrosine kinase 3 (FLT-3), colony-stimulating factor 1 receptor (CSF-1R), c-KIT, and PDGFR-α and PDGFR-β.10 Evidence of the in vivo activity of ilorasertib was confirmed in xenograft models. Concurrently, the sponsor began this solid tumour study and a separate phase 1 dose-escalation trial in patients with haematologic malignancies. The latter trial completed accrual and achieved its primary endpoints: safety, pharmacokinetics, and preliminary antitumour activity.15
We enrolled patients with diverse advanced solid tumours in a phase 1 dose-escalation trial of ilorasertib. In the early dose cohorts of the trial, adverse effects typically attributed to VEGFR inhibition were observed with greater frequency than those typically attributed to Aurora kinase inhibition. The subsequent analysis of pharmacodynamic biomarkers reported here provided evidence that maximum inhibition of VEGFR2 in the systemic vasculature occurs at lower exposures than required to inhibit Aurora kinase in tissue—concordant with the observed relationship with VEGFR2-inhibition-related adverse events. We employed measurement of fit-for-purpose clinical, plasma, and skin biomarkers to inform the future development of this single compound with multiple intended kinase targets.
Materials and methods
Study design and objectives
This was a phase 1 multicentre, open-label, dose-escalation study (NCT01110486) to evaluate the safety, pharmacokinetics, and pharmacodynamics of ilorasertib in patients with advanced solid tumours. Patients were enrolled from March 2010 to May 2012. The study was to be conducted in two distinct stages, with the first involving a dose-escalation cohort and the second an expanded safety cohort. However, due to the discontinuation of this programme, no patients were enrolled in the second stage. Dose escalation proceeded using an adaptation of the continual reassessment method16,17 with the objectives of defining dose-limiting toxicities (DLTs) and subsequent maximum-tolerated dose (MTD). The study enrolled patients into five treatment arms (I–V); Arms IV and V were combination arms in which ilorasertib was combined with carboplatin or docetaxel, respectively. Herein, we report the findings for the three monotherapy arms. All patients in Arms I, II, and III received ilorasertib monotherapy on days 1, 8, and 15 of each 28-day cycle. Ilorasertib was administered orally (PO) once daily (QD) in Arm I, PO twice daily (BID) in Arm II, and via 2-h intravenous (i.v.) infusion in Arm III. In Arm II, dosing was separated by a 6-h interval with the total dose divided into two equal daily doses. In all treatment arms, patients continued ilorasertib treatment until disease progression or toxicity related to ilorasertib that failed to resolve to grade ≤ 2 within 3 weeks. The primary objectives of the study were to determine the safety profile, evaluate the pharmacokinetics, and determine the MTD of ilorasertib monotherapy. Secondary objectives included characterisation of clinical pharmacodynamics of ilorasertib (biomarker analyses) and preliminary efficacy evaluation. All preliminary efficacy variables were exploratory in nature. The study received institutional review board approval and was conducted in accordance with International Conference on Harmonisation Good Clinical Practice guidelines, and ethical principles that have their origin in the Declaration of Helsinki. All patients provided their written informed consent.
Patient eligibility criteria
Patients aged ≥ 18 years with histologically confirmed locally advanced or metastatic solid tumours that were refractory to standard therapy were eligible. In addition, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate renal function (serum creatinine ≤ 1.5× the upper limit of normal (ULN) and either estimated creatinine clearance ≥ 50 mL/min as per Cockcroft-Gault formula or ≥ 50 mL/min based on 24-h urinalysis), liver function (serum bilirubin < 2× ULN and aspartate aminotransferase and alanine aminotransferase ≤2.5× ULN), and bone marrow function (absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and haemoglobin ≥ 9.0 g/dL), QTc interval < 500 ms on electrocardiogram, and left ventricular ejection fraction >50%.
Patients with any of the following were excluded: active central nervous system involvement including untreated brain or meningeal metastases, although patients with treated brain metastases that were radiographically or clinically stable for ≥4 weeks after therapy and had no evidence of cavitation or haemorrhage were eligible, provided they were asymptomatic and did not require corticosteroids; prior anticancer therapy within the past 21 days or five half-lives (whichever was shorter); any grade ≥ 2 unresolved toxicities from prior anticancer therapy; major surgery within past 28 days; symptomatic or persistent, uncontrolled hypertension; grade > 1 proteinuria; receiving anticoagulation therapy; or the patient had any medical condition, uncontrolled, or otherwise, which in the opinion of the investigator placed the patient at unacceptably high risk for toxicities or would limit compliance with study requirements. Concomitant use of CYP3A4 inhibitors and inducers was prohibited.
Dose and treatment schedule
Dose escalation was first conducted in Arm I and subsequently in Arms II and III. For the three arms, dosing began in a cohort of three patients, with a doubling of the dose in subsequent dose cohorts until a DLT or a grade ≥ 2 toxicity attributable to ilorasertib occurred. The pre-specified DLT criteria included any of the following events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 considered ‘possibly’ or ‘probably’ related to the administration of ilorasertib in cycle 1: grade 4 absolute neutrophil count (ANC) decrease for >7 days or grade ≥ 3 ANC decrease with fever; grade 4 platelet count decrease; grade ≥ 3 proteinuria; grade 4 infusion reaction; grade ≥ 3 asthenia/fatigue; grade 3 nausea/vomiting for ≥48 h or diarrhoea for ≥72 h despite maximum supportive care; grade ≥ 2 neurotoxicity; unexpected grade 2 toxicity which required dose modification or delay of ≥1 week. Given the known adverse effects of VEGFR2 inhibition, specific criteria for hypertension were included: >150/100 mm Hg despite 2 weeks of clinically appropriate intervention, or severe hypertension at any blood pressure reading defined as systolic >200 mm Hg or diastolic > 110 mm Hg, or symptomatic hypertension at any reading; and for decline in left ventricular ejection fraction included: absolute decline >20% from baseline and/or a reduction to <39%. Except for the above categories, all grade ≥ 3 adverse events (AEs) without a definitive alternative etiology were also considered DLTs. AEs detected or worsened in cycle 2 and beyond could be incorporated into dose-escalation decisions at discretion of the investigators and study team.
Once the first cohorts of three patients completed dosing in cycle 1, additional cohorts of a single patient at a time were treated at the new dose level in each arm, provided there were no DLTs or treatment-related toxicities exceeding grade 1. Once a grade ≥ 2 toxicity attributable to ilorasertib occurred at a given dose level, the current and all subsequent cohorts were to increase from one to three patients, and dose escalations were limited to a maximum of 50%, with specific dose levels determined by an adaptive continual reassessment method.18 The MTD was to be continually re-estimated by a logistic regression model as the dose at which the predicted DLT rate would be 30%. For the three arms, dose-escalation decisions were made after the patient(s) in a cohort completed dosing in cycle 1.
In Arm I, dosing commenced at 10 mg PO QD and was escalated to 180 mg PO QD. This initial starting dose was calculated using 1/6 of the highest non-severely toxic dose in dogs converted to human equivalent dose, using body surface area scaling and assuming a 60-kg human. Because of uncertainty of food effects on pharmacokinetics and the once-weekly schedule, treatment was administered in a fasted state. The 180-mg dose met protocol criteria for exceeding the MTD (i.e., two patients experienced DLTs) and was de-escalated to 140 mg, at which no further DLTs were reported. Enrolment to Arm I was discontinued, on the basis of the protocol-specified continual reassessment method on which MTD was to be determined. Nevertheless, cumulative evidence from the other arms of this study and the haematologic malignancies study15 suggested that DLT criteria did not accurately identify the MTD in Arm I. In phase I studies of ilorasertib in both solid tumours and haematologic malignancies, an alternate schedule of administration was evaluated, in which the once-weekly dose was divided into two consecutive daily administrations on a weekly basis. This schedule was selected due to the anticipated lower maximum observed plasma concentration (Cmax) and greater total exposure, and the possibility that tolerability would be improved under these conditions. Dose escalation proceeded in Arm II, starting at 40 mg PO BID, and stopped at the 340-mg PO BID dose, since this dose met the protocol criteria for exceeding the MTD. The first dose was administered in the fasted state. The second dose of the treatment day was administered at least 4 h after a small meal. In Arm III, dosing commenced at 8 mg i.v. over ~2 h QD and was escalated to 32 mg i.v. QD. Dosing at 32 mg i.v. QD resulted in grade 2 and 3 toxicities (not DLTs). At this point in the trial, data from the haematologic malignancies study intravenous dosing arm enabled an estimate of the absolute oral bioavailability for doses above 80 mg PO to be 12% and further enrolment in the intravenous arm of this solid tumour study was discontinued.
Safety was assessed on the basis of AEs, physical examination, vital signs, electrocardiograms, multiple-gated acquisition scans, and clinical laboratory test assessments. AEs were graded using National Cancer Institute CTCAE version 4.0.
Pharmacokinetics of ilorasertib were evaluated in the dose-escalation cohort on blood samples that were collected on cycle 1 days 1 and 15. Parameters determined: Cmax, time to Cmax (Tmax), terminal phase elimination half-life (t1/2), clearance, apparent oral clearance (CL/F), and area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUCt) and from time 0 to infinity (AUC∞). For Arm I, blood samples were collected prior to dosing and at 0.5, 1, 2, 3, 4, 6, 8, 10 or 12, and 24 h after dosing on cycle 1 days 1 and 15; of note, for institutions not able to collect the 10- or 12-h post-dose sample, the 24-h sample was replaced with 22-h and 28-h post-dose samples. In Arm II, for the first dose, blood samples were collected pre-dose and at 1, 2, 3, and 4 h post-dose on cycle 1 days 1 and 15; for the second dose, samples were collected pre-dose and at 1, 2, 3, 4, 18, and 24 h after second dose on cycle 1 days 1 and 15. In Arm III, blood samples were collected prior to infusion, at 1 h 55 min (just before end of infusion), and at 0.5, 1, 2, 4, 6, 8, 10, and 24 h after end of infusion on cycle 1 days 1 and 15; here also, for institutions not able to collect the 8-h or 10-h after-end-of-infusion samples, the 24-h sample was replaced with 22-h and 28-h post-dose samples.
The liquid chromatography (LC)-mass spectrometry (MS)/MS method was developed and validated in the Bioanalysis Department of AbbVie. Fifty microliter of human plasma (K2EDTA as anticoagulant) was fortified with 300 µL of deuterium-stable labelled internal standard and mixed well. A HybridSPE precipitation plate (50 mg/96 wells, Supelco Analytical, Munich, Germany) was used to directly load and elute (under slight vacuum) the fortified samples into a clean collection plate. Samples were dried before reconstitution with 100 µL of 20/80 (v/v) acetonitrile/water, and injected for LC-MS/MS analysis. A Halo C8 (Wilmington, DE, USA; 2.7 µm, 2.1 × 30 mm) was used on an Agilent 1290 Infinity UPLC pump (Agilent Technologies, Santa Clara, CA) to carry out the separation. An isocratic condition with 25/75/0.1 (v/v/v) acetonitrile/water/98% formic acid was used as the mobile phase. The flow rate was set to be 0.6 mL/min. An MPS 3 C (Gerstel, Mülheim an der Ruhr, Germany) autosampler was used to introduce samples onto the UPLC system. An API 4000 mass spectrometer (Applied Biosystems, Foster City, CA) was used in the multiple reactions monitoring mode for the detection and quantitation of analyte.
The method was validated per US Food and Drug Administration guidance and internal standard operating procedures. The mean bias of lower limit of quantitation was –1.8%, with a coefficient of variance of 3%. Inter-run bias of quality controls ranged from –0.6 to 8.9%, with coefficient of variance < 7.6%. All plasma lots tested for matrix effect met acceptance criteria. Total analytic recovery ranged from 62.7 to 66.4% for the analyte, with stability demonstrated for at least five freeze/thaw cycles and 24 h at room temperature, and for at least 634 days when stored at –20° C. Post-extraction stability (autosampler and batch storage) was established for at least 72 h in an autosampler set at 10° C.
Pharmacodynamic analyses were conducted to better clarify the relationships between exposure parameters and extent of engagement of the intended therapeutic targets. Biomarkers to assess ilorasertib-mediated inhibition of both VEGFR and Aurora kinase pathways were measured.
To determine whether VEGF signalling was inhibited by ilorasertib, placental growth factor (PlGF) was assessed in Arm I at baseline and 24 h post-dosing. Plasma concentrations of PlGF were determined using an automated ARCHITECT system that utilised a patented chemiluminescent detection technology called CHEMIFLEX (Abbott Diagnostics, Abbott Park, IL). This method is based on a robust, well-validated plasma assay in clinical trials.19 In all study arms, diastolic blood pressure (DBP) measurements were obtained by trained observers, consistent with American Heart Association guidelines.20
To assess inhibition of Aurora kinase B signalling during ilorasertib treatment, 3-mm skin punch biopsies were collected from patients prior to and following ilorasertib exposure (dosing at 8 mg i.v. and 120–680 mg PO (60‒340 mg PO BID)). Biopsies were formalin fixed, paraffin embedded, and the levels of phosphohistone H3 (pHH3), a direct substrate of Aurora kinase B and therefore useful for assessing Aurora kinase B activity, were measured by immunohistochemistry using anti-pHH3, 1:100 (Cell Signaling #9701, Beverly, MA). In brief, after staining, whole section images were scanned with the Aperio Scanscope XT (Aperio, Vista, CA). The number of nuclei present in the epidermal layer of skin was determined using an image analysis algorithm (Spectrum Image Analysis Program, Aperio), and the number of pHH3-positive cells was counted by a pathologist blinded to the dose arm and pre-/post-treatment status of each biopsy sample (Mosaic Laboratories, Lake Forest, CA).
Disease effect endpoints were determined using Response Evaluation Criteria In Solid Tumors version 1.1. Tumour burden assessment was conducted within 21 days prior to cycle 1 day 1, every 8 weeks thereafter, and at the final visit if not performed in the past 4 weeks.
Descriptive statistics were used for demographic variables. The numbers and percentages of patients with treatment-emergent AEs (TEAEs) were tabulated using the Medical Dictionary for Regulatory Activities version 16.0 system organ class and preferred term, and further classified according to CTCAE version 4.0 criteria. The safety data set included all patients who received one or more doses of ilorasertib. The pharmacokinetic data set included all patients who received one or more doses of ilorasertib and had one or more pharmacokinetic samples. Values for pharmacokinetic parameters were determined using non-compartmental methods, with data analysed separately for each arm. A repeated measures analysis was performed for Tmax and dose-normalised Cmax, AUCt, and AUC∞. The model included random effects for patient and fixed effects for dose level, day, and the interaction of dose level and day. To assess effects of exposure on pharmacodynamic biomarkers, Cmax was employed as the directly measured marker of exposure for the rapid changes in DBP and PlGF pre-steady-state, while AUC∞ reflected exposure variability at the time of post-multiple-dose skin biopsy. Descriptive statistics were used to summarise ECOG performance status. The efficacy data set included all patients who received one or more doses of ilorasertib.
Patient disposition and characteristics
A total of 58 patients were enrolled in Arms I (n = 23), II (n = 28), and III (n = 7). In Arm I, patients were treated at dose levels of 10 mg (n = 3), 20 mg (n = 2), 40 mg (n = 1), 80 mg (n = 3), 120 mg (n = 7), 140 mg (n = 4), and 180 mg (n = 3). In Arm II, patients received dose levels of 40 mg (n = 3), 60 mg (n = 3), 90 mg (n = 4), 130 mg (n = 4), 190 mg (n = 7), 230 mg (n = 4), and 340 mg (n = 3). In Arm III, patients were treated at 8 mg (n = 4), 16 mg (n = 1), and 32 mg (n = 2). All patients received one or more doses of study drug and thus comprised the intent-to-treat, efficacy, and safety datasets. Table 2 summarises patient demographics and baseline characteristics. Overall, patients were predominantly female (62%), self-reported race of ‘White’ (93%), aged < 65 years (69%), with a median age of 61 years (range: 35–81). All patients had advanced solid tumours; the most common were colorectal (24%) and ovarian (16%). Overall, 67% of patients had more than two prior drug regimens. All patients discontinued treatment, with the reasons for study drug discontinuation being radiologic evidence of progressive disease (64%), clinical evidence of progressive disease (14%), AEs (17%), and withdrawal of consent (7%).
TEAEs occurred in 56 of 58 (97%) patients treated with ilorasertib; grade 3 or 4 TEAEs occurred in 32 of 58 (55%) patients. The most common TEAEs reported in >20% of patients were fatigue (48%), decreased appetite (34%), hypertension (34%), nausea (26%), diarrhoea (26%), constipation (22%), and vomiting (21%). TEAEs that occurred in ≥10% of patients and grade 3 or 4 TEAEs that occurred in >2% of patients are summarised according to treatment arm in Table 3. The most common grade 3 or 4 TEAEs were hypertension (17%), diarrhoea (3%), and neutropenia (3%). Thirty-eight of 58 (66%) patients reported TEAEs that were considered possibly or probably related to ilorasertib by the investigator. The most common (≥10% of patients) treatment-related TEAEs were hypertension (29%), fatigue (24%), decreased appetite (19%), nausea (17%), diarrhoea (14%), thrombocytopenia (14%), and vomiting (10%). Sixteen (28%) patients reported grade 3 or 4 TEAEs that were considered treatment related, with the most common ( > 2% of patients) being hypertension (14%), diarrhoea (3%), and neutropenia (3%).
Treatment-emergent serious AEs were reported in 21 (36%) patients, with events occurring in >2% of patients including small intestinal obstruction (7%) and fatigue (3%). TEAEs that led to discontinuation were reported in 10 (17%) patients. However, none of these events, including hypertension, fatigue, and specific gastrointestinal events, occurred in more than one patient. TEAEs resulted in deaths of three patients, including one patient in Arm I with renal failure, and two patients in Arm II, one each with pulmonary embolism and progression of a malignant neoplasm. All three deaths occurred within 30 days of the patients discontinuing the study. Nevertheless, none of the deaths were considered related to ilorasertib by the investigator, but rather to the underlying disease or disease progression.
Six (10%) patients experienced a total of ten DLTs. In Arm I, DLTs were grade 3 abdominal pain and grade 3 fatigue, occurring in one patient each, treated at the 120-mg and 180-mg dose levels, respectively. Another patient (180 mg) had grade 3 hypertension and diarrhoea. In Arm II, DLTs were grade 3 posterior reversible encephalopathy syndrome and grade 3 leucopenia in one patient each, treated at 190-mg and 340-mg dose levels, respectively. A further patient in Arm II (340 mg) experienced grade 4 hyperuricaemia, grade 3 non-cardiac chest pain, grade 3 dehydration, and grade 3 stress-induced cardiomyopathy. In Arms I and II, ilorasertib at 180 mg QD and 340 mg BID, respectively, met the protocol criteria for exceeding the MTD. No patient in Arm III had a DLT. The sponsor’s strategic and resource allocation decisions led to study termination without establishment of the MTD. Two investigator-sponsored trials (NCT02478320 and NCT02540876), based on the findings reported in this manuscript, were ongoing at the time of manuscript submission.
Ilorasertib plasma concentration-time profiles following QD PO administration in Arm I, BID PO administration in Arm II, and QD i.v. administration in Arm III are summarised in Fig. 1 for days 1 and 15 of cycle 1. Plasma concentrations of ilorasertib in Arm I peaked at ~4 h after a single dose under fasting conditions across dose levels. In Arm II, with oral administration in two divided doses, Tmax was delayed by several hours, whereas in Arm III, with i.v. administration, Tmax was 2 h (end of infusion). The mean t1/2 after a single dose of ilorasertib was ~12 h. Ilorasertib exposures, as assessed by Cmax and AUC, were approximately dose proportional over a dose range of 10–180 mg QD in Arm I, 40–340 mg BID in Arm II, and 8–32 mg i.v. in Arm III. The mean (±s.d.) pharmacokinetic parameters of ilorasertib following QD PO administration in Arm I on days 1 and 15 of cycle 1 are summarised in Supplementary Table S1 and Supplementary Table S2, respectively. The respective data for Arms II and III are summarised in Supplementary Tables S3–S6.
Changes from baseline in DBP and PlGF following ilorasertib administration are shown in Fig. 2. DBP elevation21,22,23 (Fig. 2a, b) and increase in PlGF24,25,26 (Fig. 2c, d) reflect VEGFR2 inhibition. Increases in DBP and PlGF did not seem to be dose proportional. Based on skin biopsy samples from patients treated with ilorasertib, increasing exposure to ilorasertib resulted in dose-dependent decreases of pHH3, indicating inhibition of Aurora kinase B activity in the epidermis (Fig. 3). The maximum VEGFR inhibition was reached at lower doses and systemic concentrations than the Aurora inhibitory effects. Peak changes in DBP and PlGF were observed in the second quintile of exposure, whereas maximum pHH3 inhibition was observed at the highest exposure.
Two patients in Arm II had a partial response as their best response. Both patients had received two or more prior drug regimens. One of the responders (duration of response: 405 days) had skin cancer (basal cell carcinoma) and was treated with ilorasertib at dose of 40 mg BID. The other responder (duration of response: 168 days), with an adenocarcinoma of unknown primary site, received ilorasertib at 230 mg BID.
Pharmacodynamic biomarker/pharmacokinetic analysis revealed clinically relevant differences in the exposure/response relationships for the two intended targets of the multikinase inhibitor ilorasertib. Peak inhibition of VEGFR2 was evident by increases in DBP and plasma PlGF concentrations in the second plasma exposure quintile of ilorasertib, whereas the marker of Aurora kinase B inhibition (percentage change from baseline in pHH3 in skin biopsies) reached peak effect only in the two highest quintiles. These observations have informed the further development of ilorasertib and illuminate considerations in the development of other multikinase inhibitors.
Clinical development of novel anticancer therapeutics often assumes that the dose-limiting AEs will be mechanism-dependent events, directly related to engagement of the intended primary target of the drug. In the case of compounds that inhibit multiple targets, intensive scrutiny of the pharmacokinetic/pharmacodynamic relationships would be necessary for optimal development of the compound. We observed in this cohort of solid tumour patients that complete VEGFR2 inhibition was achieved at lower ilorasertib exposure, while maximum Aurora kinase B inhibition effects in tissue required higher exposures. These findings are consistent with cellular assays that revealed ilorasertib inhibition of VEGFR2 to be two- to five-fold more potent than for Aurora kinase B.10 But this differential in in vitro potency is unlikely to be the exclusive predictive factor of differential pharmacodynamic effects. For example, the primary site of VEGFR2 expression is in systemic endothelium, a compartment that is more rapidly and completely accessed by ilorasertib than tissue Aurora kinase B. In Arm I of this study, dose-escalation was discontinued based, in part, on development of grade 3 hypertension by one of the patients at the 180-mg dose. In the earlier study conducted in patients with haematologic malignancies,15 the DLTs were those previously associated with VEGFR2 kinase inhibitors: hypertension and pancreatitis, but detected at higher doses than in this solid tumour patient investigation. In contrast, the AE most likely to be caused by Aurora kinase inhibition, leucopenia, was routinely observed in both the haematologic and solid malignancy trials, but was not dose limiting.
These observations describe a primary challenge to the further development of ilorasertib as a multikinase inhibitor—inhibition of the intended targets typically occurs at different systemic concentrations, and toxic effects of VEGFR2 inhibition may be encountered by some patients before the potentially therapeutic effects of Aurora kinase inhibition are reached. However, differences among patients in intrinsic sensitivity to the pharmacodynamic effects of VEGFR2 inhibition have been well described.21,27 One potential strategy is to exclude patients who are intrinsically sensitive to low-exposure VEGFR2 inhibition and associated AEs, and administer full-dose ilorasertib exclusively to patients who tolerate maximum inhibition of VEGFR2. An alternative strategy would be to identify a predictive biomarker that predisposes tumours to greater sensitivity to Aurora kinase inhibition at achievable exposures. A clinical investigation based on the latter strategy is ongoing (NCT02540876).
These observations are based on retrospective analysis of prospectively collected data, but the study was not initially designed to perform this analysis. Complete data were not available for all patients, so these results could be biased in unappreciated ways. Although the blood pressure and plasma PlGF measurements were obtained with validated methods, these biomarkers of VEGFR2 inhibition have not yet been clinically qualified as measures of VEGFR2 kinase inhibition. The skin pHH3 assay employed in this study is also analytically validated and, although not functionally validated as a biomarker of pharmacologic inhibition of Aurora kinases, pHH3 inhibition has also been observed with other Aurora kinase inhibitors.28,29 Furthermore, although pHH3 inhibition may be observed in normal cells, this occurs at a reduced degree compared with highly proliferating tumour cells. We considered these reported biomarkers to be fit-for-purpose in the context of this study, but acknowledge these points and have considered them in our analysis and conclusions.
The current study confirmed previous phase 1 tolerability and safety findings of ilorasertib. Treatment of advanced solid tumour patients with ilorasertib resulted in engagement of the intended targets, but the pharmacokinetic/pharmacodynamics analyses revealed differential effects on these targets. The future development of multitargeted agents could benefit from systematic incorporation of similar pharmacokinetic/fit-for-purpose pharmacodynamic biomarker analyses into early stage investigations.
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Rini, B. I. et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumours. Clin. Cancer Res. 17, 3841–3849 (2011).
Veronese, M. L. et al. Mechanisms of hypertension associated with BAY 43-9006. J. Clin. Oncol. 24, 1363–1369 (2006).
Bass, M. B. et al. Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer. J. Clin. Endocrinol. Metab. 95, 5018–5027 (2010).
Willett, C. G. et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J. Clin. Oncol. 23, 8136–8139 (2005).
Deprimo, S. E. et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J. Transl. Med. 5, 32 (2007).
Maitland, M. L., Cardiovascular Toxicities Panel, Convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee. et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J. Natl. Cancer Inst. 102, 596–604 (2010).
Mross, K. et al. A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 78, 405–417 (2016).
Steeghs, N. et al. Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J. Clin. Oncol. 27, 5094–5101 (2009).
AbbVie and we thank the patients who participated in this clinical trial and all study investigators for their contributions. We thank Jerry Clarin, employee of AbbVie, for technical assistance in development of the pHH3 immunohistochemistry assay. Medical writing support was provided by Sandra Mendes, PhD, CMPP (TRM Oncology, The Hague, The Netherlands), funded by AbbVie Inc. (Chicago, IL, USA). AbbVie Inc. provided financial support for this study (NCT01110486) and participated in the design, study conduct, analysis and interpretation of the data, as well as the writing, review, and approval of this manuscript.
M.M., E.H., S.W., W.M., J.P., C.D., and P.A.: AbbVie employees and may own stock and/or options. G.K.L.: Contractor statistician from inVentiv Health Inc. G.F.: Has research funding from AbbVie. R.K.: Has research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant/advisory board fees from Actuate Therapeutics and XBiotech, and an ownership interest in CureMatch, Inc. M.J.R.: Consultant to AbbVie. D.H.: Has research/grant funding from Bayer, Lilly, Genentech, Loxo, Pfizer, Amgen, Mirati, Ignyta, Merck, Daiichi Sankyo, Eisai; travel, accommodations, expenses from Mirna, Loxo; consulting or advisory role with Bayer, Baxter, Guidepoint Global; other ownership interests with OncoResponse (founder). The remaining authors declare no competing financial interests.
About this article
Cite this article
Maitland, M.L., Piha-Paul, S., Falchook, G. et al. Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial. Br J Cancer 118, 1042–1050 (2018). https://doi.org/10.1038/s41416-018-0020-2
Journal of Cancer Research and Clinical Oncology (2021)
Expert Opinion on Therapeutic Patents (2021)
Frontiers in Molecular Biosciences (2020)
The synthesis and anti‐tumour properties of novel 4-substituted phthalazinones as Aurora B kinase inhibitors
Bioorganic & Medicinal Chemistry Letters (2020)


The Morning After
-Welcome To Calgary: Calle Jarnkrok played in his second game last night and was, again, robbed of his first goal. He did, however, pick up his first point with the Flames by getting an assist on Noah Hanifin's goal that put the Flames up 1-0.
-Large Work Load: Much like Jacob Markstrom, Thatcher Demko gets the lion's share of the time in the Vancouver net. Despite surrendering 4 goals and getting the hook, last night was the 19th straight time Demko appeared in a game.
-Pretty Good On The Back End: The Flames aren’t historically great in back to back contests, but this year is something different. The 5-2 victory in Vancouver last night made the Flames 7-4-1 in the second game of back to back’s this season.
Post Game Reaction
"We were pretty solid."— Calgary Flames (@NHLFlames) March 20, 2022
Darryl Sutter shares his thoughts on the win over the Canucks tonight. pic.twitter.com/C5LLkzyazA


Indian Navy Recruitment 2017
Good news for Engineers who want to join Indian Navy. Applications are invited for grant of Short Service Commission in Executive Branch in General Service/Hydro and Technical Branch (General Service/Naval Architecture) and Permanent Commission in Naval Armament Inspectorate Cadre (NAIC) in the Indian Navy for June 2018 Course. So, candidates searching for Defence Jobs in India can apply for the Indian Navy SSC Recruitment 2017. Interested candidates can apply for the vacancies at www.joinindiannavy.gov.in or from the link given below. The applicants must satisfy the eligibility conditions before applying to the Indian Navy Recruitment SSC Officer 2017. Go through this article to check more details of the selection process, physical standards, and other rules to apply for Indian Navy Recruitment 2017 for Engineers.
Moreover, the Indian Naval Recruitment board is going to conduct the written test in various regions. So, check out the dates on which the exam will be conducted in your region and apply for the Indian Navy Jobs 2017. Shortlisted candidates should attend the SSB Interview at Bangalore/ Bhopal/ Coimbatore/ Vishakapatnam. Selected individuals should work for a period of 12 years which can be extended further. Candidates selected for the SSC Recruitment in Indian Navy 2017 will get a pay scale as per their rank and according to the 7th Central Pay Commission. So, to know more details about the Indian Navy 2017 Vacancy read the below sections.
Indian Navy SSC Recruitment 2017 @joinindiannavy.gov.in
|Name of the Organization||Indian Navy|
|Name of the Post||Officer|
|Number of Vacancies||Various|
|Job Location||Across India|
|Job Category||Defecnce Jobs|
SSC Recruitment in Indian Navy 2017 Eligibility Criteria
Job seekers applying for Indian Navy SSC Engineering Vacancy 2017 must have the eligibility criteria given below.
- BE/ BTech or in the final year of BE/ BTech.
Check the notification or read the below sections for more details regarding the educational qualifications, experience.
- Candidates should not have been born between 2nd July 1993 and 1st January 1999.
Applicants who are willing to apply for Indian Navy Technical Recruitment 2017 must take the following tests as the selection process.
- Intelligence Test.
- Discussion test.
- Psychological testing.
- Group testing.
- Applicants do not have to pay any fees.
Candidates who will be selected for Indian Navy Jobs 2017 will get a pay scale according to 7th Central Pay Commission.
- Sub Lieutenant: Rs. 56,100 to Rs. 110,700 per month.
- Lieutenant: Rs. 61,300 to Rs. 120,900 per month.
- Lieutenant Commander: Rs. 69,400 to Rs. 136,900 per month.
- Commander: Rs. 121,200 to Rs. 212,400 per month.
How to Apply for Indian Navy Recruitment SSC Officer 2017
Applicants who wish to apply for the above posts must follow the steps given below.
- Applicants first visit the Official Website i.e www.joinindiannavy.gov.in.
- Go to Careers & Jobs.
- Click on become an officer and select your option.
- Read the instructions carefully.
- Check if you have the eligibility.
- On the home page go to Apply Online.
- If you are a new user click on registration and fill all the details.
- Read all the instructions carefully.
- Click on apply online.
- Give the registration number
- Fill all the details in the application form like Name, Date of Birth and various other details.
- Keep a Print out of the filled application form for future reference.
The candidates who want to apply for the officer posts in Indian Navy SSC Recruitment 2017 must have the following physical standards given below.
|Sl. No.||Branch|| Eye Sight|
Without Glasses With Glasses
|Height & Weight|
|Minimum height – 157 cm with|
|2||Technical (General Service)||6/24|
|Minimum height Male – 157 cm|
& Female – 152 cm with
- Application Starting Date: 5th August 2017.
- Application Closing Date: 25th August 2017.
- SSB Interview Date: Between November 2017 to March 2018.
|Official Notification||Apply Online Link|
|Employment News||Central Govt Jobs|


Street Car to POLAND-A pedestrian bridge over Press Street Train Tracks
This petition had 3,118 supporters
The train that crosses Press Street seems to be the biggest obstacle for getting a street car line extending down St.Claude to Poland. We propose a pedestrian bridge over the tracks as a solution. The streetcar will stop on the north side of the Press train tracks, passengers will take a stairway or elevator up to a cross walk that extends over the train tracks. Passengers will then descend down another set of stairs or elevator on the south side of the Press tracks. They will then board another street car that will travel from Press Street to Poland Avenue. This solution will save time and money compared to any other strategy that involves renegotiating the path of the train or building a train bridge to go over the tracks.
Today: Sallie is counting on you
Sallie Higgins needs your help with “Street Car to POLAND-A pedestrian bridge over Press Street Train Tracks”. Join Sallie and 3,117 supporters today.


Scientific Committee on Antarctic Research (SCAR)
Collated by Programma Nazionale di Ricerche in Antartide (Italy)
in the framework of the SCAR Standing Committee on Antarctic Geographic Information (SCAGI)
Orcho Glacier (The name as it would appear in a gazetteer)
Orcho Glacier (The name as it would appear on a map)
If this information is incorrect, please e-mail email@example.com
Feature type: Glacier (12)
This name originates from Bulgaria. It is part of the Bulgaria Gazetteer and the SCAR Composite Gazetteer of Antarctica.
The 2 km long and 1.9 km wide glacier on the E side of Ravelin Ridge on Clarence Island in the South Shetland Islands situated N of Treskavets Glacier and SSW of Banari Glacier. Flows eastwards and enters the Southern Ocean N of Gesha Point. British mapping in 1972 and 2009. Named after the Bulgarian rebel leader Orcho Voyvoda (1829-1911).
No images of this place could be found.


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CHICAGO - Three people, including a 3-year-old boy, are in critical condition Friday after an apparent gang-related shooting at a neighborhood basketball court in Chicago that left up to 13 people injured.
At least 10 ambulances were sent to the site in Chicago's Back of the Yards neighborhood after 10 p.m. Thursday, WGN-TV reports. No deaths were reported.
Police spokesman Ron Gaines said that victims were being interviewed to determine the circumstances of the shooting. As of Friday morning, no arrests have been reported.
A witness, Julian Harris, told the Chicago Sun-Times that dreadlocked men fired at him from a gray sedan before turning toward Cornell Square Park and firing at people. He said his 3-year-old nephew was wounded in the cheek.
"They hit the light pole next to me, but I ducked down and ran into the house," Harris said. "They've been coming round here looking for people to shoot every night, just gang-banging stuff. It's what they do."
The Chicago Tribune quotes police as saying the boy suffered a gunshot wound to the head at an ear that exited through his mouth. Chicago Fire Department officials said he was in critical condition. The Tribune quotes family members as identifying the boy as Deonta' -- pronounced Deontay -- who was nicknamed Tay Man.
Officials at Mount Sinai hospital said Friday that the boy was a patient there but could not provide an update on his condition. Two other victims were also in critical condition. The others were reported in serious to fair condition.
Officer Amina Greer Greer told the Associated Press early Friday that police have since identified a 13th victim, a 33-year-old woman with a gunshot wound to the back near one shoulder. Other victims included a 15-year-old and a 17-year-old. The injuries ranged from shots to the heads to wounds in the knee and buttocks.
Police also said the shootings appeared to be gang-related.
"Senseless and brazen acts of violence have no place in Chicago and betray all that we stand for," Mayor Rahm Emanuel said in a statement Friday. "The perpetrators of this crime will be brought to justice and prosecuted to the full extent of the law. I encourage everyone in the community to step forward with any information and everyone in Chicago to continue their individual efforts to build stronger communities where violence has no place."
Three weeks ago an outbreak of violence during the Labor Day weekend left eight people dead and 20 injured.
The Chicago police department responded by paying overtime to add patrols to some neighborhoods, including the Back of the Yards, where Thursday's shooting took place.
Crime statistics released this week by the FBI showed that Chicago, with 500 murders in 2012, replaced New York, with 419, as the murder capital of the U.S.

domain: sociology


'Game of Thrones' Star Peter Vaughan Dead at 93
'Game of Thrones' Star Dead at 93
12/6/2016 6:35 AM PT
Peter Vaughan, the veteran British actor who gained a new following with his recurring role on "Game of Thrones" ... died Tuesday morning.
Vaughan's agent says the actor died peacefully this morning around 10:30 surrounded by his family. Vaughan played Maester Aemon -- the former leader of the Night's Watch -- on the hit show from 2011 until 2015.
During his 75 years in show biz ... Vaughan starred in several British TV series and feature films. He co-starred with the likes of Sir Anthony Hopkins, Clive Owens, and Frank Sinatra.
Vaughan was 93.


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Discover your ideal property on Hvar, stress-free.
With our comprehensive property Search & Acquisition service, we specialise in assisting international clients in finding their ideal holiday home or investment property. Our end-to-end support ensures a seamless experience from start to finish. Leveraging our extensive local expertise, firsthand knowledge, and valuable connections, we guide you through the process, expertly steering clear of the pitfalls frequently encountered by less experienced buyers.
Why We Do It
Visitors to this beautiful island sometimes imagine that purchasing a property here will be a pathway to effortless profits through rental or resale, along with the added perk of free accommodation for their vacations. While the Hvar real estate market offers remarkable opportunities in an undeniable paradise, many obstacles await the overconfident and underprepared.
Navigating the intricacies of purchasing property in Croatia involves a distinct set of legal and regulatory processes, rife with potential challenges where even a small oversight can result in immense stress and disappointment.
Introducing Hvar Away's Search & Acquisition service. Led by Matt and supported by a team of Approved Solicitors and experts, we serve as your knowledgeable guides from the inception of your property search to the final legal acquisition – and without question, always prioritising your best interests throughout the journey.
How We Do It
Our 6-step process clarifies your property purchase journey, guiding you from initial exploration right through to the keys in your hand, ensuring a smooth process throughout.
2. First Consultation
We'll then arrange our initial consultation, either in person on the island or through a convenient video call.
During this meeting, our primary focus will be to ensure a thorough understanding of your detailed requirements beyond the questionnaire responses, provide answers to the questions you will have, and enable us to best deliver on your expectations.
1. Profiler Questionnaire
We begin by sending you our detailed Property Profiler Questionnaire, comprehensively analysing your preferences and objectives – whether it's a personal holiday home, an investment property, or a harmonious blend of both.
Clear understanding is paramount as we strive to fulfil your requirements completely.
3. Property Portal
With the search initiated, we revert to our extensive contacts and insider knowledge to explore properties that align with your criteria, including those not officially listed on the market. Once a preliminary selection of properties is compiled, they are uploaded to your personalised Property Portal. This dynamic platform provides real-time updates, ensuring you stay informed as new information becomes available. Upon reviewing the options in your portal, you can indicate which properties you wish to consider further. Our Approved Solicitor will step in, conducting essential due diligence to scrutinise the properties' ownership.
5. Price Negotiation
Get ready for an exciting phase as we progress to the next stage. If you decide to move forward, we will present an offer to the seller on your behalf, bringing all of our expertise to the negotiation process to secure the most advantageous deal possible.
With our on-the-ground connections, we can typically identify the best way to achieve the sale at the best price. We will always remain committed to positioning ourselves to ensure the best possible deal for you. This is a significant advantage you would be unlikely to attain without the assistance of a Search and Acquisition service. Unlike traditional agencies in Croatia, where the dynamics may differ, our primary objective is to secure the lowest price for you. We relentlessly strive to have your offer accepted on terms that meet your best interests.
4. Viewings & Reports
After the first due diligence process, the number of potential property options in your portal is typically refined, resulting in a curated shortlist of remaining properties.
Subsequently, an in-person visit is carried out at the shortlisted properties to gather comprehensive information and prepare a detailed Property Report. This report, with extensive photography, video content, and including drone footage, provides you with a comprehensive understanding and insight into the property and its surroundings.
Following the Property Report's upload to the portal, we look forward to receiving your valuable feedback. Additionally, if desired, you have the option to arrange an on-site visit to explore the property firsthand.
6. Completion Assistance
Once the seller accepts your offer, our Approved Solicitor conducts the full and final due diligence, ensuring nothing is overlooked. Subsequently, if necessary, the solicitor will present a purchase pre-contract agreement, which will be agreed as a purchase proposal. In cases where a pre-contract agreement is not required, the solicitor will move straight to drafting the purchase contract. Upon the contract's completion, the solicitor initiates the necessary procedures with the land registry to facilitate smooth transfer of ownership.
Throughout this critical legal acquisition phase, we remain focused on your purchase, overseeing the entire process, providing constant support and communication. From monitoring change of ownership submissions to ongoing contact with the solicitor, we are on hand to resolve any last-minute issues, ensuring you remain well-informed until the keys are in your hand. Time to celebrate!
Our commitment extends beyond the acquisition process. Should you require assistance with property renovation, within our range of property services we offer comprehensive project management and convenient home installations, including air conditioning, off-grid solar solutions, and electrical projects. Looking ahead, our Hvar Assured packages guarantee that your property remains in excellent condition for years to come, providing ongoing maintenance and upkeep.
A one-time payment of €500 is required upon instruction and prior to commencing a search, valid for up to 6 months. This retaining fee is fully deductible from the success fee.
Upon the legal completion of the sale, a success fee of 1.9% of the purchase price is applicable. Alternatively, if the savings negotiated between the documented asking price and the final purchase fee amount to 12% or more, the success fee will be calculated based on the greater value.
Our transparent pricing structure is set out below.
Book Your Consultation
Take the first step towards finding your ideal property on Hvar by booking a consultation with Matt.
First, we'll email you over our Property Profiler Questionnaire so we can have a more detailed conversation about your unique requirements, answer your questions, and provide personalised guidance tailored to your needs.
Whether you're seeking a luxurious holiday home or a lucrative investment opportunity, our first consultation will set you on the path to realising your Hvar real estate aspirations.

domain: law


text:
Polls are raising questions about whether all college-aged adults will choose to get a coronavirus vaccine when one is available.
Conference is first Division I league to postpone its fall football season, which some believe could influence other institutions' plans.
As many colleges prepare to continue teaching at least partially online this fall, student advocacy groups such as the Institute for College Access and Success (TICAS) are ramping up calls for greater scrutiny of the modality.
The new Department of Homeland Security rule prohibits international students from returning to or remaining in the United States if their colleges adopt an online-only instruction model for the fall.
City University of New York laid off 2,800 adjunct professors and part-time staff members last week. The union representing the employees responded by suing the university system.
College athletes are leading boycotts and prompting conversations about racial injustice. They're also embracing their power to initiate change at their institutions and beyond.
Researchers at Cornell University have concluded an online semester at the university will result in more COVID-19 infections than an in-person one.
Professors across institutions are increasingly waving red flags about the private and public health implications of default face-to-face instruction come fall, along with a lack of shared decision making in staffing and teaching decisions.
Trump administration elevates skills over college degrees in federal hiring, but college groups say executive order will not lessen value of degrees.
Park University is encouraging students from other institutions to transfer and study online for a year at a discounted tuition rate. Are special offers like this a good idea?

domain: news


Install Favorites for Aurélien Pupier
EGit is the Git integration for Eclipse. Git is a distributed versioning system, which means every developer has a full copy of all history of every revision of the code, making queries against the...
SCM, Team Development, Code Management
Last Updated on Tuesday, December 27, 2016 - 17:43 by Chris Aniszczyk
Tools, Source Code Analyzer
Last Updated on Thursday, March 8, 2018 - 12:22 by Julien HENRY
MoreUnit is an Eclipse plugin that should assist you in writing more unit tests. It supports all programming languages (switching between tests and classes under tests...) and has specific support ...
Last Updated on Saturday, March 3, 2018 - 15:25 by Vera Henneberger
Infinitest is a continuous test runner for Java, and is valuable to developers using a unit testing tool called JUnit. Continuous testing is the practice of constantly running unit tests while deve...
Last Updated on Monday, November 7, 2016 - 14:20 by David Gageot
This simple tool provides refactorings that simplifies test creation by converting non-existing variables into field or local Mockito mocks.
Convert non-resolvable variable i...
Tools, IDE, Testing
Last Updated on Monday, November 7, 2016 - 14:09 by Michal Borek


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What is Noble Corporation's stock symbol?
Noble Corporation trades on the New York Stock Exchange (NYSE) under the ticker symbol "NE."
How often does Noble Corporation pay dividends? What is the dividend yield for Noble Corporation?
Noble Corporation announced a quarterly dividend on Friday, July 22nd. Stockholders of record on Monday, August 1st will be paid a dividend of $0.02 per share on Monday, August 8th. This represents a $0.08 annualized dividend and a dividend yield of 1.09%. The ex-dividend date of this dividend is Thursday, July 28th.
Where is Noble Corporation's stock going? Where will Noble Corporation's stock price be in 2017?
31 equities research analysts have issued twelve-month price objectives for Noble Corporation's shares. Their forecasts range from $4.00 to $16.00. On average, they expect Noble Corporation's share price to reach $7.97 in the next year.
When will Noble Corporation announce their earnings?
Noble Corporation is scheduled to release their next quarterly earnings announcement on Tuesday, April, 25th 2017.
What are analysts saying about Noble Corporation stock?
Here are some recent quotes from research analysts about Noble Corporation stock:
- Jefferies Group LLC analysts commented, "On NE specifically, despite shares being up 24% YTD as of 1/25/17, we still see the stock as having upside and believe NE is the best vehicle for anybody trying to play recovery in the space at this point (it doesn't screen as overvalued on a relative basis through the modeled period, FCF generation looks solid, and it remains less expensive than peers on a normalized basis). NE isn't immune from the lack of catalysts in the sector. However, despite the company taking actions in December to improve the Balance Sheet, the new CFO may still pursue additional measures to strengthen the capital structure (such as using asset backed-financing on one or more of their term contracts), which we would view as a positive. Similar to RDC, NE has 'good' UDW and high spec jackup assets with availability that should return to work relatively earlier in the upcycle. However, unlike in RDC's case, we don't see Consensus as being overly generous about the profitability of a market turn..." (1/30/2017)
According to Zacks Investment Research, "Noble Corporation's robust portfolio of assets, long-term commitments and strong backlog offer some relief in the currently weak pricing scenario. In particular, the company’s strong operational execution and cost-management efforts are noteworthy. However, uncertainty lingers over new contract flows and dayrates. Also, Noble Corp. has a large number of rigs coming off contracts and securing new contracts for those could be a challenge in the present conditions. Further, the oversupplied rig market remains a challenge for offshore drilling firms. So, until the uncertainty and volatility in oil prices subside, we see limited upside for NE shares from current levels." (10/27/2016)
Argus analysts commented, "We are lowering our 2016 EPS estimate to $0.61 from $0.89, reflecting continued energy sector weakness and the substantial downturn in drilling activity. We are widening our 2017 loss estimate to $0.42 from $0.11 per share, which assumes further deterioration in energy industry fundamentals next year. The 2016 consensus EPS estimate is $0.62 and the 2017 consensus loss forecast is $0.53 per share."He continued, "As Noble winds down its newbuild program, it should begin to generate higher free cash flow. (The company took delivery of 11 rigs in 2013 and 2014, and expects one additional rig to be delivered in 2016.) Over the last three years, NE's annual capital spending has averaged $2.1 billion. However, management expects capex of $800 million in 2016, including the $461 million to be paid on delivery of the final rig, which is scheduled for 3Q16." (5/20/2016)
Who owns Noble Corporation stock?
Noble Corporation's stock is owned by many different of institutional and retail investors. Top institutional investors include State Street Corp (5.65%), Dimensional Fund Advisors LP (5.39%), Alyeska Investment Group L.P. (3.41%), Marshall Wace LLP (2.07%), Van ECK Associates Corp (1.07%) and Allianz Asset Management AG (0.85%). Company insiders that own Noble Corporation stock include Bernie G Wolford, Mary P Ricciardello, Michael A Cawley and Scott Marks.
Who sold Noble Corporation stock? Who is selling Noble Corporation stock?
Noble Corporation's stock was sold by a variety of institutional investors in the last quarter, including Oxford Asset Management, Alyeska Investment Group L.P., Numeric Investors LLC, Allianz Asset Management AG, Kovitz Investment Group Partners LLC, Franklin Resources Inc., GSA Capital Partners LLP and Federated Investors Inc. PA. Company insiders that have sold Noble Corporation stock in the last year include Mary P Ricciardello and Michael A Cawley.
Who bought Noble Corporation stock? Who is buying Noble Corporation stock?
Noble Corporation's stock was purchased by a variety of institutional investors in the last quarter, including State Street Corp, Dimensional Fund Advisors LP, Marshall Wace LLP, Renaissance Technologies LLC, J. Goldman & Co LP, Guggenheim Capital LLC, Flinton Capital Management LLC and Tyers Asset Management LLC.
How do I buy Noble Corporation stock?
Shares of Noble Corporation can be purchased through any online brokerage account. Popular online brokerages include Vanguard Brokerage Services, TD Ameritrade, E*TRADE, Scottrade, Fidelity and Charles Schwab.
How much does a share of Noble Corporation stock cost?
One share of Noble Corporation stock can currently be purchased for approximately $7.36.

domain: finance


In addition to providing the highest quality testing instruments for the pulp and paper industry, Technidyne has made the added commitment to provide our customers with the most economical solutions possible.
At times Technidyne is positioned as the testing instrument with the lowest cost in the marketplace. At other times the economic benefit can be measured over the entire life of a product. This value is measured by looking at the product itself, the calibration materials, on-going preventative maintenance and service, and the impressive history of instrument longevity Technidyne is known for.
Technidyne customers evaluate their investment by looking at the cost benefits over the entire life of the product, not just the initial capital investment. One of our goals it to provide the most economical return on investment over the entire life of our products helping customers meet their budgetary needs while exceeding their functional measurement and accuracy needs.
Technidyne preventative maintenance ensures that our products remain in a better condition and provide more accurate data over time. This is not just a result of our technicians having their hands on the instrument for calibration and maintenance, there is also much value in the communication and support that happens between our customers and our technicians during these visits. The transfer of knowledge and expertise is often invaluable. This also improves our understanding of the inner workings of your mill as well as your priorities and goals making Technidyne a partner focused on your specific needs at all times.
Learn more about the economic and functional benefits of Technindyne instruments or contact a Technidyne representative today using our Global Directory.


text:
Blonde Is Difficult to Watch Despite Ana De Armas' Stellar Performance
The movie, based on the private life of Marilyn Monroe is heartbreaking to watch.
Netflix recently launched their much-hyped movie on Marilyn Monroe.
There were enough reasons to get excited about the movie. The cast, led by Ana De…


text:
A reader expresses disapproval about politicians that are ignoring the advice of medical experts. Also: Lamont’s choice of words; creating an improved society
Callous disregard of fellow citizens is neither responsible nor patriotic
Entering the eighth week of impositions on our daily routines because of COVID, demands for the elimination of restrictions, often with threats of violence, are increasing. Unfortunately, some politicians, ignoring all respected medical advice, are giving in to these demands.
Those demanding an immediate return to normalcy claim to want their “freedoms” returned; many wrap themselves in the flag while doing so. While they have every right to demonstrate, these protestors display little knowledge of the Constitution, or of patriotism.
Our Constitution grants, to every citizen, precious rights. What some seem to ignore is that there are responsibilities that accompany those rights. In the exercise of your rights, you have a responsibility not to infringe on my rights, or the rights of society as a whole. Callous disregard of ones fellow citizens is neither responsible nor patriotic.
Twenty years ago, Tom Brokaw authored “The Greatest Generation,” a tribute to the sacrifices millions of patriotic citizens made during World War II. Imagine if, after eight weeks, Americans had decided to abandon that war because we were tired of the loss of life, gas rationing, blackouts and other restrictions that it imposed. Were Brokaw to write the history of the current crisis, if restrictions are ended prematurely, it would have to be entitled “The Selfish Generation.”
Raymond Pech, Barkhamsted
Gov. Lamont’s words are not those of a leader
One would think that someone in a position of state leadership could articulate his feelings with a little more emotional maturity. Instead, the leader of this state chose derision over respect for those concerned about the harmful effects of his policies stating that, “you should be free to be dumb if you want to. But not if it endangers others.”
Gov. Ned Lamont’s own policies, while intended to save lives, objectively endanger others. Lost wages and the failure of the government to fund unemployment for those affected has unarguably been devastating for thousands in Connecticut, and the long term physical and mental health implications of restricting daily activity and the denial of elective surgeries are staggering.
That aside, Lamont’s dismissal of the people he works for as “dumb” is deeply saddening. It is not required for Lamont to agree with the protesters, but it is required that he not dismiss them outright if he wishes to be a good leader. Sadly, Lamont’s leadership is clearly lacking. His words are not those of a leader. They are, well, dumb.
One thing that has struck me about Connecticut since moving here is the politeness of its people, the diversity of opinion, and the respect everyone has for each other. In Connecticut, we may disagree, but we do it respectfully. Not once since I have moved here have I heard anyone called dumb. Ned Lamont may represent our beautiful state in government, but he does not do so in spirit.
Robert Miller, West Hartford
The ingredients for a better society
I am deeply moved by the loving acts of kindness that have been displayed during this pandemic. Perhaps the silver lining is an opportunity to reflect and reevaluate what is really important in life.
We have here a teachable moment that reminds us that cooperation, tolerance and appreciation are the ingredients for a better society. All people are worthy of respect and dignity, no matter their race, religion or vocation. I hope that out of this sorrow might emerge a more enlightened world.
Our lives are a journey. Along the way there are obstacles, challenges and adversity, as well as joy, love and fulfillment. We derive our values and truths from our own experiences, both good and bad; yet when we are able to step outside of our own experiences and into the shoes of others, we leave judgmental thinking behind and walk side by side, together, with empathy and compassion.
Jeff Grande, West Hartford


text:
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Unforgettable poetic imagery by one of the greatest female African American poets that captures the viality and complexity of Black life.
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Airmax Remote Manifold
The Airmax Pond & Lake Remote Manifold Assembly Kit is a great addition to any Airmax Aeration System when the power source is a long distance away from the edge of the pond. The kit allows pond owners to run a single direct burial line from the power source to the pond. The multi-port system lets you adjust the airflow of each plate at the edge of the pond so you can see the difference in an instant.


Hana Brooks broke onto the indie pop scene during November 2017 and now returns with her new track ‚Used To Be‘, where a heartbreaking vocal is layered on a groove of urban bass and beats, tropical synths and ambient guitars.
Brooks‘ debut release ‚Leave It‘ was reviewed and playlisted globally over 40 times, gaining airplay in the USA and Europe.
The music video, filmed in California, and live streamed performance collectively picked up 50,000 hits on facebook in 2 days.
The new release ‚Used To Be‘ is picking straight up where the previous single left off and has been produced and mixed by Nick Bennett ( London Grammar / Asgeir ) .
To support the release a launch party at the world – renowned music club The Troubadour in Earls Court, London UK on 28th February 2018
Hana is now working on two new songs with Daniel Green, co-producer and mix engineer on Coldplay’s most recent album ‘A Head Full of Dreams’. They are working in Coldplay’s personal studio The Bakery in Hampstead, where the likes of Viva la Vida was written and recorded.


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Bridgit Mendler "Hurricane" Acoustic Live Performance
Bridgit Mendler performs her single "Hurricane" from her new album 'Hello My Name Is.' Get the backstory of the song straight from Bridgit her self in ClevverTV's music show "Off the Charts."
Appears on these pages
"Hurricane" is a song by American recording artist Bridgit Mendler, taken up from the former's...

domain: artistic


text:
Finding Your Way to Your Authentic Career
The vast majority of people are actively dissatisfied – or, at best, unfulfilled – by their current jobs. The reasons span a wide range. Some simply experience a bad fit with the career fate steered them into; others fear their expertise will have little relevance to in the future we’re headed into. Whatever the cause, most workers express a desire to switch into an entirely different profession if given the opportunity to do so. If you’re one of these folks, this book is for you. And its overall message is: Your purpose is out there waiting for you. There is indeed a methodical process you can use to find it, and to transition successfully over to it. There’s little about this process that is novel or complex. It doesn’t require you to spend a lot of money. It doesn’t require you to go through any special training beforehand. It just asks you to have the commitment and courage to progress through all of its steps. If you do, the odds of you ending up with a clear understanding of your “purpose” – and in a job that’s consistent with it – are extremely good. Probable, even. Your authentic work is out there waiting. Now it’s time for you to go find it.

domain: literature


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Newspapers reported that the federal government would permit as much as 5,000 international drivers into Britain on short-term visas, a measure that logistics firms and retailers have demanded for months however which the federal government had beforehand dominated out.
The UK’s Street Haulage Affiliation (RHA) says Britain wants 100,000 extra drivers whether it is to satisfy demand. The motive force scarcity has been brought about partly by Brexit and Covid-19, and the lack of a couple of yr of driver coaching and testing.
“We’re momentary measures to keep away from any fast issues, however any measures we introduce can be very strictly time restricted,” a spokeswoman for Johnson’s Downing Avenue workplace mentioned in a press release.
Downing Avenue declined to provide additional particulars.
Ministers have cautioned towards panic shopping for, and oil firms say there is no such thing as a scarcity of provides, merely issues delivering the gas to the gasoline stations.
Nevertheless, lengthy strains of automobiles have begun gathering at petrol stations to replenish after BP mentioned it needed to shut a few of its retailers because of the driver shortages.
Some Shell stations have additionally reported pumps working dry whereas ExxonMobil’s Esso has additionally mentioned a small variety of its 200 Tesco Alliance retail websites had additionally been impacted ultimately.
EG Group, which runs tons of of forecourts throughout Britain, mentioned on Friday it might impose a purchase order restrict of £30 ($41) per buyer for gas because of the “unprecedented buyer demand.”
“We’ve ample gas shares on this nation and the general public ought to be reassured there aren’t any shortages,” the Downing Avenue spokeswoman mentioned.
“However like international locations all over the world we’re affected by a short lived Covid-related scarcity of drivers wanted to maneuver provides across the nation.”
Britain says the long-term answer is for extra British drivers to be employed, with the RHA saying higher pay and situations are wanted to draw individuals into the business.
However the retail business has warned that until the federal government acts to deal with the scarcity within the subsequent 10 days, then vital disruption is inevitable within the run-up to Christmas.


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I came late to Don Van Vliet. Listening to Doc at the Radar Station in summer ‘ 99 at the peak of my infatuation with post-punk and its antecedents, I was prepared for its wrenching guitar sound and quicksand textures, but not the sheer oddness of the Captain’s vocals. “Telephone” and “Sue Egypt” still sound frightening late at night driving home — fuck the guitars and Moogs. Other than a cursory listen to the less involving Ice Cream For Crow, I ignored Beefheart until, fittingly, this time last year, when I downloaded Shiny Beast (Bat Chain Puller), accounted his best by fans indifferent to Trout Mask Replica. What struck me, ten years after my first listen and cognizant of Pere Ubu, was how damn catchy the thing sounded. Another lesson I’d learned from loving Ubu’s Cloudland for years: the insistence on “linear” songwriting actually made the artists sound stranger. At odd times I’d hum “Tropical Hot Dog” and “Harry Irene” to myself; the former sounds like dotty Rupert Holmes.
Now I guess I’ll listen to Trout Mask Replica: a “classic” record I managed to politely ignore for years.
As a postscript, here’s Lester Bangs’ interview with Beefheart from the late seventies. The artist’s way with the English language is as astounding as his chordal structures.


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Who doesn’t love to go on a thrilling boat ride across serene backwaters; listening to the little murmurs of Nature and watching it bloom in all its glory. There is never a boring second when you go boating, especially with friends and family. As a destination that is blessed with various waterbodies including canals and lakes, Kozhikode has for a passionate visitor many boating avenues at some of the most exotic locations in the district.
The waterbodies of Kozhikode are famed for their illustrious beauty. Gently cruising through the placid waters, enjoying the charming beauty of the locale around, is indeed an experience of a lifetime. River Kallai is one destination that is famed for boating. Traditionally Kallai was an important water-route through which goods reached Kozhikode. Though some of those activities still exist to this day, boating as a tourism entertainment isn’t all that old. Elathur is another spot where you can go boating through amazing locales covered in lush greenery. Canolly Canal is another waterbody which was once the main route of cargo transport between Kozhikode and Kochi. Today, it is an idyllic route where you can enjoy some pleasant boating experiences. You can also go boating at other blissful locations such as Kakkayam and Kalipoika.

domain: travel


text:
Recently one of our 2019 Scholarship Recipients Taylah Gerecke spoke to Wodonga Senior Secondary College students alongside Alanah Osingna.
Taylah and Alanah spoke to female Wodonga Senior Secondar
Madeline Jackson from Gulgong, Apprenticeship in Engineering and Fabrication.
Today is the day The Riverina Lions Women's AFL remember two of their girls a little more then every
The Sarah Lloyd Scholarship Fund is proud to present to you all the Recipients of 2019.
(Left to Right)
Madeline Jackson from Gulgong
Apprenticeship in Engineering and Fabrication
Come down to watch the girls play! A game to celebra
To everyone involved in Wagga Wagga Takes 2 for 2019 - Over $450,000 raised!
Our very own Tracey Lloyd, you smash
"What an awesome couple of days "Our Sarah Lloyd Scholarship volunteers were busy over Easter & ANZAC Day. Cooking up a storm & the onions, down at Bunnings Wagga!
For the month of February, The Sarah Lloyd Scholarship Fund has been given a donation jar at
A big thank you to all the business to date who have so kindly donated merchandise or their services to our Auction. Check back soon to see what other goodies have been added.


-----BEGIN PGP SIGNED MESSAGE----- Hash: SHA1
Xen Security Advisory CVE-2014-3967,CVE-2014-3968 / XSA-96 version 3 Vulnerabilities in HVM MSI injection
The implementation of the HVM control operation HVMOP_inject_msi, while checking whether a particular IRQ was already set up in the necessary way, fails to properly check all respective conditions. In particular it doesn't check the returned pointer for being non-NULL before de- referencing it. (CVE-2014-3967)
Furthermore that same code also handles certain errors by logging messages, without (under default settings) at least making these messages subject to rate limiting. (CVE-2014-3968)
The NULL pointer de-reference would lead to a host crash, and hence a denial of service would result. Since host and guest page tables are fully separated for HVM guests, the guest would not be able to leverage the vulnerability for other kinds of attacks (privilege escalation or information leak).
The spamming of the hypervisor log could similarly lead to a denial of service.
In a configuration where device models run with limited privilege (for example, stubdom device models), a guest attacker who successfully finds and exploits an unfixed security flaw in qemu-dm could leverage the other flaw into a Denial of Service affecting the whole host.
In the more general case, in more abstract terms: a malicious administrator of a domain privileged with regard to an HVM guest can cause Xen to become unresponsive leading to a Denial of Service.
All Xen versions from 4.2 onwards are vulnerable.
The vulnerability is only exposed to service domains for HVM guests which have privilege over the guest. In a usual configuration that means only device model emulators (qemu-dm).
In the case of HVM guests whose device model is running in an unrestricted dom0 process, qemu-dm already has the ability to cause problems for the whole system. So in that case the vulnerability is not applicable.
The situation is more subtle for an HVM guest with a stub qemu-dm. That is, where the device model runs in a separate domain (in the case of xl, as requested by "device_model_stubdomain_override=1" in the xl domain configuration file). The same applies with a qemu-dm in a dom0 process subjected to some kind kernel-based process privilege limitation (eg the chroot technique as found in some versions of XCP/XenServer).
In those latter situations this issue means that the extra isolation does not provide as good a defence (against denial of service) as intended. That is the essence of this vulnerability.
However, the security is still better than with a qemu-dm running as an unrestricted dom0 process. Therefore users with these configurations should not switch to an unrestricted dom0 qemu-dm.
Finally, in a radically disaggregated system: where the HVM service domain software (probably, the device model domain image) is not always supplied by the host administrator, a malicious service domain administrator can exercise this vulnerability.
Running only PV guests will avoid this vulnerability.
In a radically disaggregated system, restricting HVM service domains to software images approved by the host administrator will avoid the vulnerability.
This issue was discovered by Jan Beulich.
Applying the attached patch resolves this issue.
xsa96.patch xen-unstable, Xen 4.4.x, Xen 4.3.x, Xen 4.2.x
$ sha256sum xsa96*.patch 1b64beddf8f6e9c08af24676551c18fd778a8db65a6c24fec07cc7e95531e2af xsa96.patch $ -----BEGIN PGP SIGNATURE----- Version: GnuPG v1.4.12 (GNU/Linux)
iQEcBAEBAgAGBQJTj0MHAAoJEIP+FMlX6CvZY04H/1Udj8OzkKHHxaCLQWxAUo6w SCSV37MNRQcsJJly4KAUjsO+yyfNPnVQBUsVsBcSnKURElbkYf1IaBGSPWbiiTZY ubtQgT/rF8y0cShvDiCVXP7giwHN270F3YIXAvZPn/ZvM0a6Wad6VbBEgIo6vUeU vqb10LnrKy7S7h8sVaQCIuM5/6ysjtJAyDtlFyDN55J4socHD+oYTtU+HNbZZFvs UytIy56dtO5TSkazKgCZR936BWreYl4izOy1+elLM+r8k0qz8SdTdcVzVqNqYkMK QxjwiM7cy4fZxi1R+N/mwXgyr2tv2r/6AsdCX3vuZreg/Dp4Fi+7lDnj/sfBSGg= =fTzY -----END PGP SIGNATURE-----


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Also, LARB’s Eric Newman drops in to recommend two books from the recent Chinese LGBT canon: Notes of a Crocodile by Qiu Miaojin from Taiwan and Beijing Comrade by Bei Tong — both of which brilliantly capture the spirit of romantic obsession. The wide-ranging conversation includes Soviet space dogs, humanity’s betrayal of the planet, the relevance of Latin American literature in the era of Trump, and of course, the reason this moment inspires protest. LARB Radio Hour: Janet Sarbanes’s “The Protester Has Been Released”; Plus Recent Chinese LGBT Literature
By LARB AV – May 11, 2017
Author Janet Sarbanes speaks with Kate and Medaya about her new collection The Protester Has Been Released.