Specific Endpoints Research Articles

An experimental study on photothermal damage to tissue: the role of irradiance and wavelength

Laser exposure time and irradiance are crucial parameters governing the process of thermal damage. The goal of our in vitro study was to study and determine optimal parameters for the onset of coagulation and carbonization at three different wavelengths (980, 1070 and 1940 nm). We also compared photothermal effects at these three wavelengths by varying laser exposure time and irradiance. Fresh bovine liver specimens were used for experimentation. The onset of thermal damage at different irradiances and for different exposure time was studied macroscopically and histologically. Photothermal damage or lesion volume generally decreased with irradiance and increasing exposure time. We observed an exponential and linear relationship between irradiance and exposure time for specific thermal endpoints. These specific endpoints were the onset of (i) coagulation, and (ii) carbonization. The time interval or difference between these specific endpoints termed as Δt (tcarbonization − tcoagulation) (s) was also determined. This relation between irradiance and exposure time will make possible the pre-estimation of thermal tissue lesion volume before operation, and photothermal therapy may thus be performed with minimum side effects on liver tissue.

Can Toxicity for Different Species be Correlated?

Experimental evaluation of the toxicity of a compound is an expensive practice, and it requires sacrifice of a large number of animals. As a consequence, in silico techniques for predictive toxicology are taking the central stage of attention of the scientific community. Interspecies quantitative structure-toxicity relationship (i-QSTR) modeling provides a tool for estimation of contaminant's sensitivity with known levels of uncertainty for a diverse pool of species. It is capable of extrapolating data for one toxicity endpoint to another toxicity endpoint when the data for the second species are unavailable. The emerging i-QSTR approach can overcome the cost of multiple toxicity tests, improve the understanding of the mechanism of toxic action (MOA) of chemicals for different organisms and endpoints and is very useful in order to fill the data gaps where toxicity value for a particular compound is absent for a specific endpoint.

Glasgow Blatchford, pre-endoscopic Rockall and AIMS65 scores show no difference in predicting rebleeding rate and mortality in variceal bleeding

Objective: To compare the performance of the Glasgow Blatchford score (GBS), pre-endoscopic Rockall score (PRS) and AIMS65 score in predicting specific clinical endpoints following variceal upper gastrointestinal hemorrhage (UGIH).Material and methods: Between January 2008 and December 2013, we retrospectively analyzed 225 consecutive hospitalized patients managed for endoscopically confirmed UGIH.Results: A total of 225 patients (mean age 61.3 years), mostly diagnosed with alcoholic cirrhosis (195/86.7%), presented with variceal UGIH during the study period. Rebleeding occurred in 22 (9.8%) patients and 30-day mortality was 39 (17.3%). Initial hemostasis was achieved with N-butyl cyanoacrylate (151/79.1%) and endoscopic variceal ligation (40/20.9%), while secondary rebleeding prophylaxis in 110 (48.9%) patients was accomplished using endoscopic variceal ligation (92%). The majority of patients died from the underlying disease, while 12 (30.8%) died from bleeding. Median hospital stay was 6 (1–35) days. There was no statistically significant difference among AIMS65, GBS and PRS in predicting mortality (AUROC 0.70 vs. 0.64 vs. 0.66) or rebleeding rates (AUROC 0.74 vs. 0.60 vs. 0.67). The GBS was superior in predicting the need for blood transfusion compared to AIMS65 score (AUROC 0.75 vs. 0.61, p = 0.01) and PRS (AUROC 0.75 vs. 0.58, p = 0.009).Conclusions: The AIMS65, GBS and PRS scores are comparable but not useful for predicting outcome in patients with variceal UGIH because of poor discriminative ability. The GBS is superior in predicting the need for transfusion compared to AIMS65 score and PRS.

Novel chemical hazard characterisation approaches

There is a fundamental change in thinking within the regulatory community due to a better understanding of the underlying biology of adverse effects to human health and the environment. The development of alternatives to use laboratory animals has become a priority. In addition, technological progress is impacting greatly on the amount of data available and on the ways to process and analyse it. Topics, such as identification of adverse outcome pathways (AOPs) and modes of action (MoA), together with integrated assessment and testing approaches (IATAs), represent fundamental tools for hazard identification and characterisation of a chemical. Complex endpoints cannot be predicted by a single standalone non-animal test; thus, a major challenge is the complex nature of biological systems. Microphysiological systems (MPS) will enable more complex in vitro human models that better simulate the organ's biology and function by combining different cell types in a specific three-dimensional configuration that simulates functional organs. The process of validation of new approaches needs to be considered in terms of efficiency and length. Regulators might still not have enough confidence to adopt and apply these new approaches: this phase is very challenging and the activities performed by assay developers are not yet addressing the regulatory requirements needs sufficiently. The IATAs provide a framework to consistently evaluate new approach data and could assist in understanding their relevance for specific endpoints. The data need to be reproducible, understandable and statistically sound: indeed, a major issue lies in the interpretation and integration of the results based on subjective assessment, which relies on expert judgement. A well-defined mechanistic characterisation is proposed as a way forward to ensure the relevance of new cell-based test systems.

Incorporating Sex As a Biological Variable in Neuropsychiatric Research: Where Are We Now and Where Should We Be?

Understanding the multiplicity of ways in which sex can alter the brain is essential to crafting policies and treatments that are beneficial for all human beings. This is particularly true for the field of neuropsychopharmacology, as many neuropsychiatric disorders exhibit gender bias in the frequency, severity, or response to treatment. The goal of this circumspective is to provide two views on the current state of the art of the relations between sex and the brain, relations that are studied almost exclusively by comparing females and males on specific end points, from gene expression to behavior. We start by suggesting a framework for defining what is being measured and what it means. We suggest that 'sex differences' can be classified on four dimensions: (1) persistent vs transient across the lifespan; (2) context independent vs dependent; (3) dimorphic vs continuous; and (4) a direct vs an indirect consequence of sex. To accurately classify a sex difference along these dimensions, one may need to compare females and males under varied conditions. We next discuss current data on the mechanisms of sexual differentiation of the brain and on sex differences in the brain to conclude that the brain of each male and female is a mosaic of relative masculinization, feminization, and sameness, which theoretically could produce an infinite variety of individuals. We also raise the possibility that sex differences in the brain are canalized, which may act to both enhance and restrain variation between males and females. We end by discussing ways to consider sex when studying neuropsychiatric disorders.

PROSPERA: a randomized, controlled trial evaluating rasagiline in progressive supranuclear palsy.

To date, pharmacological treatment options for progressive supranuclear palsy (PSP), a neurodegenerative tauopathy, are limited. The MAO-B inhibitor rasagiline has shown neuroprotective effects in preclinical models of neurodegeneration. To evaluate the safety, tolerability and therapeutic effect of rasagiline on symptom progression in PSP. In this 1-year randomized, double-blind, placebo-controlled trial, 44 patients fulfilling the NINDS-PSP criteria were randomized to 1mg/d rasagiline or placebo. The combined primary endpoint included symptom progression as measured by the PSP rating scale (PSP-RS) and the requirement of L-dopa rescue medication. Secondary endpoints included Schwab and England Activities of Daily Living (SEADL), Montgomery-Åsberg Depression Rating Scale, Mini Mental State Examination, Frontal Assessment Battery and posturographic measurements. Of the 44 patients randomized, 26 completed the trial per protocol. Rasagiline was well tolerated, with a slight increase of known side effects (hallucinations, ventricular extrasystoles). No effect on the primary endpoint (p=0.496) was detected. Symptom progression averaged at 11.2 (rasagiline) and 10.8 (placebo) points per year (ΔPSP-RS). No difference was seen in SEADL, depression, cognitive function, frontal executive function and posturographic measurements. Post hoc analyses of PSP-RS subdomains indicate a potential beneficial effect in the "limb motor" subdomain, whereas performance appeared lower in the "mentation" and "history" subdomains in the treatment group. While rasagiline is well tolerated in PSP, a beneficial effect on overall symptom progression was not detected. Post hoc analyses suggest the implementation of more specific endpoints in future studies.

Special endpoint and product specific considerations in pharmaceutical acceptable daily exposure derivation

Recently, a guideline has been published by the European Medicines Agency (EMA) on setting safe limits, permitted daily exposures (PDE) [also called acceptable daily exposures (ADE)], for medicines manufactured in multi-product facilities. The ADE provides a safe exposure limit for inadvertent exposure of a drug due to cross-contamination in manufacturing. The ADE determination encompasses a standard risk assessment, requiring an understanding of the toxicological and pharmacological effects, the mechanism of action, drug compound class, and the dose-response as well as the pharmacokinetic properties of the compound. While the ADE concept has broad application in pharmaceutical safety there are also nuances and specific challenges associated with some toxicological endpoints or drug product categories. In this manuscript we discuss considerations for setting ADEs when the following specific adverse health endpoints may constitute the critical effect: genotoxicity, developmental and reproductive toxicity (DART), and immune system modulation (immunostimulation or immunosuppression), and for specific drug classes, including antibody drug conjugates (ADCs), emerging medicinal therapeutic compounds, and compounds with limited datasets. These are challenging toxicological scenarios that require a careful evaluation of all of the available information in order to establish a health-based safe level.

Co-delivery of GPI-anchored CCL28 and influenza HA in chimeric virus-like particles induces cross-protective immunity against H3N2 viruses

Influenza infection typically initiates at respiratory mucosal surfaces. Induction of immune responses at the sites where pathogens initiate replication is crucial for the prevention of infection. We studied the adjuvanticity of GPI-anchored CCL28 co-incorporated with influenza HA-antigens in chimeric virus-like particles (cVLPs), in boosting strong protective immune responses through an intranasal (i.n.) route in mice. We compared the immune responses to that from influenza VLPs without CCL28, or physically mixed with soluble CCL28 at systemic and various mucosal compartments. The cVLPs containing GPI-CCL28 showed in-vitro chemotactic activity towards spleen and lung cells expressing CCR3/CCR10 chemokine receptors. The cVLPs induced antigen specific endpoint titers and avidity indices of IgG in sera and IgA in tracheal, lung, and intestinal secretions, significantly higher (4–6 fold) than other formulations. Significantly higher (3–5 fold) hemagglutination inhibition titers and high serum neutralization against H3N2 viruses were also detected with CCL28-containing VLPs compared to other groups. The CCL28-containing VLPs showed complete and 80% protection, when vaccinated animals were challenged with A/Aichi/2/1968/H3N2 (homologous) and A/Philippines/2/1982/H3N2 (heterologous) viruses, respectively. Thus, GPI-anchored CCL28 in influenza VLPs act as a strong immunostimulator at both systemic and mucosal sites, boosting significant cross-protection in animals against heterologous viruses across a large distance.

Thrombin Generation Assay and Its Application in the Clinical Laboratory.

A gap exists between in vivo and ex vivo coagulation when investigated by use of the coagulation tests prothrombin time (PT) and activated partial thromboplastin time (APTT). The thrombin generation assay (TGA) has been developed to fill this gap. TGA evaluates thrombin generation (resulting from the action of the procoagulant driver) and decay (resulting from the action of the anticoagulant driver), thus assessing the balance between the two. Coagulation of the test plasma (platelet poor or platelet rich) is activated by small amounts of tissue factor and phospholipids, and the reaction of thrombin generation is continuously monitored by means of a thrombin-specific fluorogenic substrate. Among the parameters derived from the thrombin-generation curve, the most important is the endogenous thrombin potential, defined as the net amount of thrombin that test plasmas can generate on the basis of the relative strength of the pro- and anticoagulant drivers. TGA is therefore the candidate assay to investigate hypo- or hypercoagulability. From my analysis of the literature, I draw the following conclusions. There is strong evidence that TGA is helpful to elucidate coagulation mechanisms in various clinical conditions that until recently were poorly understood (chronic liver disease; diabetes; inflammatory bowel disease, myeloproliferative neoplasms, nonalcoholic fatty liver disease). TGA is a promising laboratory tool for investigating hemorrhagic coagulopathies and monitoring replacement therapy in hemophiliacs, predicting the risk of recurrent venous thromboembolism after a first event, and monitoring patients on parenteral or oral anticoagulants. These applications require clinical trials in which TGA results are combined with specific clinical end points.

Using the Bayesian network relative risk model risk assessment process to evaluate management alternatives for the South River and upper Shenandoah River, Virginia

We have conducted a series of regional scale risk assessments using the Bayesian Network Relative Risk Model (BN-RRM) to evaluate the efficacy of 2 remediation options in the reduction of risks to the South River and upper Shenandoah River study area. The 2 remediation options were 1) bank stabilization (BST) and 2) the implementation of best management practices for agriculture (AgBMPs) to reduce Hg input in to the river. Eight endpoints were chosen to be part of the risk assessment, based on stakeholder input. Although Hg contamination was the original impetus for the site being remediated, multiple chemical and physical stressors were evaluated in this analysis. Specific models were built that incorporated the changes expected from AgBMP and BST and were based on our previous research. Changes in risk were calculated, and sensitivity and influence analyses were conducted on the models. The assessments indicated that AgBMP would only slightly change risk in the study area but that negative impacts were also unlikely. Bank stabilization would reduce risk to Hg for the smallmouth bass and belted kingfisher and increase risk to abiotic water quality endpoints. However, if care were not taken to prevent loss of nesting habitat to belted kingfisher, an increase in risk to that species would occur. Because Hg was only one of several stressors contributing to risk, the change in risk depended on the specific endpoint. Sensitivity analysis provided a list of variables to be measured as part of a monitoring program. Influence analysis provided the range of maximum and minimum risk values for each endpoint and remediation option. This research demonstrates the applicability of ecological risk assessment and specifically the BN-RRM as part of a long-term adaptive management scheme for managing contaminated sites. Integr Environ Assess Manag 2017;13:100-114. © 2016 SETAC.

Critical Review of Health Impacts of Wildfire Smoke Exposure.

Background:Wildfire activity is predicted to increase in many parts of the world due to changes in temperature and precipitation patterns from global climate change. Wildfire smoke contains numerous hazardous air pollutants and many studies have documented population health effects from this exposure.Objectives:We aimed to assess the evidence of health effects from exposure to wildfire smoke and to identify susceptible populations.Methods:We reviewed the scientific literature for studies of wildfire smoke exposure on mortality and on respiratory, cardiovascular, mental, and perinatal health. Within those reviewed papers deemed to have minimal risk of bias, we assessed the coherence and consistency of findings.Discussion:Consistent evidence documents associations between wildfire smoke exposure and general respiratory health effects, specifically exacerbations of asthma and chronic obstructive pulmonary disease. Growing evidence suggests associations with increased risk of respiratory infections and all-cause mortality. Evidence for cardiovascular effects is mixed, but a few recent studies have reported associations for specific cardiovascular end points. Insufficient research exists to identify specific population subgroups that are more susceptible to wildfire smoke exposure.Conclusions:Consistent evidence from a large number of studies indicates that wildfire smoke exposure is associated with respiratory morbidity with growing evidence supporting an association with all-cause mortality. More research is needed to clarify which causes of mortality may be associated with wildfire smoke, whether cardiovascular outcomes are associated with wildfire smoke, and if certain populations are more susceptible.Citation:Reid CE, Brauer M, Johnston FH, Jerrett M, Balmes JR, Elliott CT. 2016. Critical review of health impacts of wildfire smoke exposure. Environ Health Perspect 124:1334–1343; http://dx.doi.org/10.1289/ehp.1409277

Development of a combined method to assess the complex effect of atrazine on sex steroid synthesis in H295R cells

The aim of the study was to develop a rapid, cost-effective combined testing method to assess the indirect effect of compounds interfering with sex steroid synthesis and to determine complex effects of atrazine on estrogen and androgen synthesis in vitro on H295R human cell line. Steroidogenic assay was performed on H295R human adrenocortical carcinoma cell line. Instead of standard analytical methods, bioluminescence bioreporter assays (Saccharomyces cerevisiae BLYES and BLYAS) were used to measure estrogenic and androgenic effects of sex steroid hormones released by human cells in response to atrazine. Atrazine resulted in elevated estrogen production presumably due to its well documented inductive effect on aromatase on H295R cell line, detected by BLYES. Interestingly, results of BLYAS test showed concentration-dependent increase of androgen production in H295R cells. That indicates that atrazine can not only increase estrogen level via aromatase induction, but may interfere in androgen synthesis as well. The combined method allows us to assess the androgenic and estrogenic effect of sex steroids produced by human cells in increased or decreased quantity as a result of the different chemicals, without determining specific analytical measurement endpoints, by using the yeast based bioluminescent bioreporter test.

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review.

Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments.

Enhancing active surveillance of prostate cancer: the potential of exercise medicine.

Active surveillance (AS) is a strategy for the management of patients with low-risk, localized prostate cancer, in which men undergo regular monitoring of serum PSA levels and tumour characteristics, using multiparametric MRI and repeat biopsy sampling, to identify signs of disease progression. This strategy reduces overtreatment of clinically insignificant disease while also preserving opportunities for curative therapy in patients whose disease progresses. Preliminary studies of lifestyle interventions involving basic exercise advice have indicated that exercise reduces the numbers of patients undergoing active treatment, as well as modulating the biological processes involved in tumour progression. Therefore, preliminary evidence suggests that lifestyle and/or exercise interventions might have therapeutic potential in this growing population of men with prostate cancer. However, several important issues remain unclear: the exact value of different types of lifestyle and exercise medicine interventions during AS; the biological mechanisms of exercise in delaying disease progression; and the influence of the anxieties and distress created by having a diagnosis of cancer without then receiving active treatment. Future studies are required to confirm and expand these findings and determine the relative contributions of each lifestyle component to specific end points and patient outcomes during AS.

Hematopoietic growth factors in lung cancer.

Most patients affected by lung cancer are treated with chemotherapy, and hence are at risk of myelosuppression. Hematopoietic growth factors have a relevant role in this setting, as they can improve quality of life, reduce the rate of chemotherapy-induced complications and allow the administration of full-dose chemotherapy. Most data of hematologic growth factors in lung cancer come from dated publications or large trials involving different malignancies, thus limiting specific information for lung neoplasms. Nonetheless, most studies consistently identified myeloid growth factors as effective on specific end-points such as the duration and severity of neutropenia, or complications such as hospitalizations and febrile neutropenia; on the other hand, erythropoiesis-stimulating agents (ESAs) consistently improved anemia-specific end-points including hemoglobin values, transfusions rate and fatigue, although some specific safety issues characterized this drug class. The most recent international guidelines address these characteristics and include the main indications for hematologic growth factors in solid neoplasms, including lung cancer. Myeloid growth factors and ESAs have a relevant role in selected patients undergoing chemotherapy for nonsmall cell lung cancer and small cell lung cancer. Notably, a comprehensive risk-benefit assessment is required in the specific case of ESAs.

Shedding blood: anemia and adverse events after percutaneous coronary intervention (PCI).

Substantial evidence from epidemiological studies suggests strong association between baseline anemia and worse outcomes following percutaneous coronary intervention (PCI) for both stable coronary artery disease (CAD) and acute coronary syndromes (ACS) (1-3). The existing data, almost exclusively from prospective analysis of clinical cohorts or retrospective post-hoc analysis of data from large randomized clinical trials designed to investigate other specific endpoints, point to anemia as a strong independent predictor of major adverse cardiac outcomes (MACE), major bleeding and mortality in patients undergoing PCI (4-6). Some of the published studies have utilized rigorous statistical methods to adjust for all known and measurable variables that can interact with anemia, nevertheless the associations inferred from these studies, while providing valuable insights, remain hypothesis generating.

In Vivo Cardiotoxicity Induced by Sodium Aescinate in Zebrafish Larvae.

Sodium aescinate (SA) is a widely-applied triterpene saponin product derived from horse chestnut seeds, possessing vasoactive and organ-protective activities with oral or injection administration in the clinic. To date, no toxicity or adverse events in SA have been reported, by using routine models (in vivo or in vitro), which are insufficient to predict all aspects of its pharmacological and toxicological actions. In this study, taking advantage of transparent zebrafish larvae (Danio rerio), we evaluated cardiovascular toxicity of SA at doses of 1/10 MNLC, 1/3 MNLC, MNLC and LC10 by yolk sac microinjection. The qualitative and quantitative cardiotoxicity in zebrafish was assessed at 48 h post-SA treatment, using specific phenotypic endpoints: heart rate, heart rhythm, heart malformation, pericardial edema, circulation abnormalities, thrombosis and hemorrhage. The results showed that SA at 1/10 MNLC and above doses could induce obvious cardiac and pericardial malformations, whilst 1/3 MNLC and above doses could induce significant cardiac malfunctions (heart rate and circulation decrease/absence), as compared to untreated or vehicle-treated control groups. Such cardiotoxic manifestations occurred in more than 50% to 100% of all zebrafish treated with SA at MNLC and LC10. Our findings have uncovered the potential cardiotoxicity of SA for the first time, suggesting more attention to the risk of its clinical application. Such a time- and cost-saving zebrafish cardiotoxicity assay is very valid and reliable for rapid prediction of compound toxicity during drug research and development.

From the MONICA-project via KORA to the NAKO-study: Practical Utility of Epidemiological Studies in Augsburg Region

The objective of the WHO-MONICA study was to determine the influence of changing risk factors and treatment options on myocardial infarction rates in populations in a 10-year time period. For this purpose, a population-based myocardial infarction registry was established in 1984 in Augsburg (covering the city of Augsburg and 2 adjacent counties) in order to continuously register all inhabitants of the region who had a myocardial infarction during the study period. In addition, three cross-sectional studies based on random population samples (1984/85, 1989/90 and 1994/95) were carried out. Our data revealed a continuous decrease of myocardial infarction incidence and demonstrated that the decrease of coronary mortality can be ascribed to decreasing myocardial infarction incidence and longer survival after myocardial infarction. Until today the myocardial infarction registry continues to be a permanent part of the Cooperative Health Research in the Region of Augsburg (KORA). Moreover, within the framework of KORA, a fourth population-based cross-sectional study was carried out in 1999/2001. Meanwhile, more than 18 000 study participants have been followed-up for specific endpoints for up to 30 years. A large number of publications, which address cardiovascular diseases, type 2 diabetes mellitus, lung diseases, environmental and genetic questions, health services research and numerous other topics, are based on the KORA study. Today we know that the development of chronic diseases can be ascribed to a complex interaction of social factors, health policy conditions, health behavior, risk factors and molecular mechanisms. To tackle the challenges posed by these multiple factors in Germany, NAKO (Nationale Kohorte), the largest nation-wide long-term study so far, was initiated. Within the framework of the NAKO study, 200 000 persons aged between 20 and 69 years in Germany - thereof 20 000 persons in the region of Augsburg - will be examined and interviewed in the next 10 years, and widespread diseases will be investigated with modern epidemiological methods. The results of these epidemiological long-term studies will contribute to the prevention, early diagnosis and best possible treatment of widespread diseases.

Abstract OT1-03-05: A phase III, randomized, open label, multicenter, controlled trial of niraparib versus physician's choice in previously- treated, HER2 negative, germline BRCA mutation-positive breast cancer patients. An EORTC-BIG intergroup study (BRAVO study)

Abstract Background Germline BRCA mutations (gBRCAmut) amongst breast cancer (BC) patients ranges between 5% - 25% depending on family history of BC or ovarian cancer (OC). Cells treated with PARP inhibitors (PARPi) accumulate defects that lead to their death in the absence of homologous recombination (HR) repair (e.g. gBRCAmut). Niraparib is a PARPi in development. As the TNT study showed better results of 1st line carboplatin vs docetaxel in gBRCAmut patients, a rise of a platinum-exposed population is expected. Due to prior experience in OC where platinum sensitivity of HR deficient cells is linked with PARPi sensitivity, it seems that patients who progress on or soon after platinum should be excluded from PARPi therapy, without sparing from PARPi those who may retain sensitivity. The protocol was amended to include platinum-exposed patients. Trial Design Bravo is a multicenter (North America, Europe &Israel) EORTC & BIG phase III trial sponsored by TESARO. Patients with gBRCAmut will be randomized (2:1) to niraparib (per os) vs physician's choice (PC) (eribulin or capecitabine or gemcitabine or vinorelbine)-NCT01905592. Eligibility Criteria • Patients with deleterious/suspected deleterious gBRCAmut locally or centrally. Central confirmation will be done. If post inclusion, based on a previous test, mutation is not centrally confirmed, they can participate based on their physician/own preference. • Up to 2 prior chemotherapy lines for metastatic disease (MD). • Previously untreated for MD are allowed if they relapse during/within 12 months of (neo-) adjuvant chemotherapy. • Prior therapy must include a taxane and/or anthracycline. Previously received platinum in the MD can be enrolled if they did not progress while on or within 8 weeks from the last day of the platinum administration. Those who received (neo-) adjuvant platinum are eligible, if relapsed 12 or > months after the last platinum dose. Specific aims Primary endpoint is PFS assessed by blinded central review . Secondary are OS, safety, PFS on local investigator assessment, time to treatment failure, response & duration of response, health- related quality assessments & tests for companion diagnostic test development. Statistical methods The PFS analysis will be done after 232 PFS events in the population of centrally confirmed gBRCAmut randomized patients. Assuming that median PFS is 3 months for PC & 6 months for niraparib (hazard ratio=0.5), there is 99.6 % power (1- sided alpha=0.025) to detect a difference from 3 - 6 months. Sample size ensure power for an OS comparison. Assuming an increase in OS from 9 -13 months, with a hazard ratio of 0.69, there is 80% power at 1- sided alpha of 0.025 when 265 deaths are observed. Assuming 40% of patients will be randomized based on local test and 15% won't be mutated centrally, an over-enrollment of 18 patients is needed to obtain the 306 in the efficacy population. A futility interim analysis will happen at 40% of PFS events. Present accrual and target accrual 1200 patients will be registered & 306 randomized. Accrual will finish in 2 years. Citation Format: Balmana J, Tryfonidis K, Audeh W, Goulioti T, Slaets L, Agarwal S, Lema N, Cameron D, Turner N. A phase III, randomized, open label, multicenter, controlled trial of niraparib versus physician's choice in previously- treated, HER2 negative, germline BRCA mutation-positive breast cancer patients. An EORTC-BIG intergroup study (BRAVO study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-05.

Abstract OT1-03-15: The METRIC trial: A randomized international study of the antibody-drug conjugate glembatumumab vedotin (GV or CDX-011) in patients with metastatic gpNMB-overexpressing triple-negative breast cancer (TNBC)

Abstract Background Glycoprotein NMB (gpNMB) is an internalizable transmembrane protein overexpressed in approximately 20% of breast cancer (BC), including approximately 40% of TNBC. gpNMB is a poor prognostic marker in BC (Rose CCR 2010) and preclinically has been implicated in tumor invasion, metastasis, and angiogenesis. GV is a novel antibody-drug conjugate targeting the potent cytotoxin monomethylauristatin E (MMAE) to gpNMB overexpressing cancer cells. In a Phase I/II study and the Phase II "EMERGE" study, GV demonstrated promising activity with TNBC patients (pts) deriving the greatest benefit and exhibiting the highest degree of gpNMB overexpression. GV was well-tolerated with the most frequent treatment-related toxicities consisting of rash, neutropenia, and neuropathy. In subset analyses of the EMERGE trial, objective response rate (ORR) was 30% (7/23) for GV vs. 9% (1/11) for investigator's choice in tumors with gpNMB overexpression (>25% of tumor epithelium); 18% (5/28) vs. 0% (0/11) in TNBC; and 40% (4/10) vs. 0% (0/6) in gpNMB-overexpressing TNBC for GV and IC respectively, with apparent improvements in progression-free survival (PFS; hazard ratio (HR) = 0.11) and overall survival (OS; HR = 0.14). Trial design The METRIC Trial (NCT#01997333) is an international (USA, CA, Aus), two-arm phase II study. Pts are randomized 2:1 to GV (1.88 mg/kg IV q 21 days) or capecitabine, a current standard of care for this population (2,500 mg/m2 daily for d1-14, q21 days) until progression or intolerance. Crossover is not permitted. Eligibility criteria Key eligibility criteria include: >25% of tumor epithelium gpNMB+ by central immunohistochemistry (IHC) screening of archival tissue; estrogen receptor and progesterone receptor <10% and HER2 negative [0-1+ IHC, or ISH copy number <4.0/ratio <2.0] by local assessment; ECOG 0-1; taxane resistance; anthracycline exposure (if indicated); <2 chemotherapy regimens for advanced BC; measurable disease; no persistent Grade >2 toxicity. Specific aims The primary endpoint is PFS per independent, blinded central review committee according to RECIST 1.1. Secondary endpoints are ORR, duration of response, OS, safety, pharmacokinetics and pharmacodynamics. Exploratory endpoints are quality of life and/or cancer-related pain. Statistical methods and target accrual The trial has 85% power to detect a PFS HR of 0.64 with two sided α = 0.05. The hypothesized median PFS is 4.0 months for capecitabine and 6.25 months for GV. Target accrual is open for 300 pts. Citation Format: Melisko M, Yardley DA, Blackwell K, Forero A, Ma C, Montero A, Daniel BR, Wright G, Fehrenbacher L, Chew H, Ferrario C, Nanda R, Seiler Jr M, Guthrie T, Vance K, Ouellette G, He Y, Bagley RG, Zhang J, Vahdat LT. The METRIC trial: A randomized international study of the antibody-drug conjugate glembatumumab vedotin (GV or CDX-011) in patients with metastatic gpNMB-overexpressing triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-15.