Articles de revues sur le sujet « Committees of safety »

Maintaining confidentiality of emerging data and ensuring the independence of Data Monitoring Committees are best practices of considerable importance to the ability of these committees to achieve their mission of safeguarding the interests of study participants and enhancing the integrity and credibility of clinical trials. Even with the wide recognition of these principles, there are circumstances where confidentiality issues remain challenging, controversial or inconsistently addressed. First, consider settings where a clinical trial’s interim data could provide the evidence regulatory authorities require for decisions about marketing approval, yet where such a trial would be continued post-approval to provide more definitive evidence about principal safety and/or efficacy outcomes. In such settings, data informative about the longer term objectives of the trial should remain confidential until pre-specified criteria for trial completion have been met. Second, for those other than Data Monitoring Committee members, access to safety and efficacy outcomes during trial conduct, even when presented as data pooled across treatment arms, should be on a limited “need to know” basis relating to the ability to carry out ethical or scientific responsibilities in the conduct of the trial. Third, Data Monitoring Committee members should have access to unblinded efficacy and safety data throughout the trial to enable timely and informed judgments about risks and benefits. Fourth, it should be recognized that a mediator potentially could be useful in rare settings where the Data Monitoring Committee would have serious ethical or scientific concerns about the sponsor’s dissemination or lack of dissemination of information. Data Monitoring Committee Contract Agreements, Indemnification Agreements and Charters should be developed in a manner to protect Data Monitoring Committee members and their independence, in order to enhance the Data Monitoring Committee’s ability to effectively address their mission.

In an increasing number of recent major clinical trials, independent safety committees or safety monitors have been involved Their role and function is not yet defined and continues to evolve. The aim of this paper is to discuss the role and tasks of safety committees as a result of our collective experience as members of three safety committees of studies evaluating antithrombotic prophylaxis against postoperative deep vein thrombosis. We believe that the type of pharmacological intervention used is of less importance than the general experiences gained, which can be extrapolated to other studies and should stimulate a more general debate.

Background and Purpose: Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees’ independence and effectiveness. Methods: An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees. Results and Conclusions: Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee’s independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

Abstract Of increasingly relevance in public health and research projects involving human beings, the topic of safety has been intensely discussed. Participants in clinical trials are subject to risks, physical or otherwise, that impact their integrity, rights, or autonomy. This study outlines and discusses the performance of the Data and Safety Monitoring Committee for research participant protection and risk minimization in clinical research. An integrative literature review was conducted to identify the committees’ duties and role in protecting participants. Most of the analyzed articles confirm that the monitoring committees are mainly responsible for protecting research participants, as well as ensuring research integrity and credibility.

Public awareness of hospital misadventure is now common. In response, we describe our integrated hospital safety system, which is dependent on the linkage of multiple individual safety committees, and the presence on each committee of senior and junior multidisciplinary healthcare professionals to provide feedback to their peer groups on required improvements.

Abstract Background: High-dose chemotherapy followed by autologous stem cell transplantation (SCT) is the current standard of care for myeloma patients for attaining deeper responses. Generic melphalan formulations that were used for more than half a century were susceptible to several challenges (marginal solubility, limited chemical stability after reconstitution and prone for hydrolysis, requirement of propylene glycol as a co-solvent, etc). Evomela™, a Captisol®-stabilized propylene glycol-free melphalan preparation recently obtained FDA indication for use as a high-dose conditioning treatment prior to SCT in patients with myeloma. However, no comparative data relative to conventional melphalan exists. The objective of our study was to evaluate if Evomela™, a more stable compound, can potentially be delivered at the intended dose and deliver higher response rates relative to melphalan. We also reviewed the safety of Evomela™ compared to the generic formulation in this retrospective analysis. Methods: This is a retrospective analysis comparing 2 sequential cohorts of myeloma patients that underwent autotransplant at a single institution. Our institution switched to Evomela™ on September 15th 2016. Approximately 201 patients received a single autotransplant with Evomela™ from September 15th 2016 until September 14th 2017. The control group (193 patients) received conventional melphalan from September 15th 2015 until September 14th 2016. Both Evomela™ and the conventional melphalan were administered on the same day of transplant with the same amount of infusion time. Patient characteristics, toxicity and responses at day 100 were collected and compared between the 2 groups. Fischer's exact and Cochran-Mantel-Haenszel tests were used to compare responses and toxicities. Results: Median age of the patients is 62 years (range 16-78). Patient and transplant characteristics were summarized in Table 1. Both of the groups are balanced, except for 2 variables. The Evomela™ group had higher rates of patients with CAD and 8% more patients received RVD induction therapy. All of the pre-transplant parameters, conditioning regimens and median CD34+ cells infused were similar. The post-SCT ≥VGPR rate was significantly higher for Evomela™ relative to melphalan (85.3% vs 78%, p=0.043), especially when the ≥VGPR rates prior to SCT were similar across the 2 groups (58.5% vs 56.5%, p=0.381), Fig 1. While the difference is seen for both 200 mg/m2 (63.8% vs 54.8%) as well as 140 mg/m2 (91.9% vs 80.4%), the ∆ change (pre-SCT VGPR to post-SCT VGPR) is highly significant among patients receiving Evomela™ 140 mg/m2 vs melphalan (37.5% to 91.9% for ∆ 54.4% vs 61.7% to 80.4% for ∆ 18.7%, p<0.001). Higher rates of neutropenic fevers were seen in the Evomela™ group (p=0.032) but the safety profile, day 30 transplant related mortality, readmission rates, ICU transfers and cardiac complications were similar to melphalan, as outlined in Table 2. Conclusions: These results suggest that by using Evomela™ the intended dose of the alkylating agent is delivered when compared to the conventional melphalan formula. Considering the similar complication rates and safety profile while obtaining higher and deeper response rates supports the use of Evomela™. Disclosures Kaufman: BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Waller:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Kalytera: Consultancy; Cambium Medical Technologies: Consultancy, Equity Ownership; Celldex: Research Funding. Heffner:Kite Pharma: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: Research Funding. Lonial:Amgen: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

PURPOSE To describe the rationale for independent data monitoring committees (DMCs) for National Cancer Institute (NCI)-sponsored phase III cooperative group clinical trials. DESIGN We review the necessity for interim monitoring of outcome data during the course of randomized clinical trials and summarize the reasons for establishing DMCs with requisite expertise and with appropriate independence from study investigators. RESULTS The important components of the policy for cooperative group DMCs are described with a focus on the makeup of these bodies and on the complementary roles of study committee leadership and DMCs in protecting patient safety during the conduct of randomized clinical trials. CONCLUSION The cooperative group DMCs that are independent of the study committees and that have the requisite expertise to examine accumulating data and to base decisions on monitoring guidelines that are specified in advance by the study committee provide a body able to protect patient safety, to protect the integrity of the clinical experiments on which patients have consented to participate, and to assure the public that conflicts of interest do not compromise either patient safety or trial integrity.

Dans tous les pays industrialises occidentaux, les reformes de la législation et des politiques gouvernementales ont commence à insister sur l'importance d'assurer la participation active des travailleurs à la planification et à la mise en œuvre de programmes et de politiques de santé et de sécurité aux lieux du travail. Les comites paritaires de santé et de sécurité au Canada sont devenus la manifestation la plus valable de la participation ouvrière à de tels programmes. Ces comités confèrent aux travailleurs et également aux employeurs une façon importante de collaborer à la prévention et à la solution des risques professionnels. Ils peuvent réunir tout un train d'expériences pratiques et de connaissances techniques, fournir des outils de communication à la main-d’œuvre et en recevoir d'elle, faciliter la contribution des travailleurs et des employeurs aux décisions auxquelles parviennent les membres des comités. Et ces comités offrent les avantages de conseils directs et continus et constituent ainsi une réponse immédiate aux risques professionnels. La nécessité de rapports de coopération plus suivis entre le travail et le patronat, spécialement en ce qui a trait à la santé et à la sécurité professionnelles peut être considérée comme une conséquence de l'incapacité séculaire de l'industrie à se discipliner et du gouvernement à adopter des normes de santé et de sécurité valables. Certains observateurs soutiennent que les gouvernements ont aussi manque à leur devoir de mettre en vigueur et de promouvoir ces normes de façon adéquate. Les principales mesures pour accroitre le degré de participation directe des travailleurs en tant que moyen d'améliorer la santé et la sécurité professionnelles sont : a) l'information en matière de santé et de sécurité ainsi que l'éducation; b) des stimulants et des pénalisations économiques (comme l'indemnisation des travailleurs) et c) l'adoption et la mise en vigueur de normes de santé et de sécurité professionnelles. Les insuffisances de ces politiques sont apparentes lorsqu'on considère les statistiques disponibles relatives aux maladies et aux accidents industriels. Chacune de ces politiques est un fouillis de contraintes et de difficultés pratiques. Une analyse des politiques et des programmes des treize compétences canadiennes en ce domaine laisse voir qu'il existe des différences notables entre les obligations et les fonctions des comités et un écart profond en ce qui a trait au degré d'appui que les gouvernements leur accordent pour assurer leur efficacité. Néanmoins, il est évident que les comités paritaires aux lieux du travail sont des facteurs de plus en plus importants dans la diminution des risques pour les travailleurs canadiens. L'insuccès admis des modes les plus traditionnels d'aborder la santé et la sécurité industrielles signifie qu'on devrait faire une plus grande confiance à la coopération patronale-ouvrière. Le nombre des comités paritaires de santé et de sécurité s'accroitra sans doute dans l'avenir. Les employeurs et les travailleurs devront en favoriser le développement. En effet, ces comités reçoivent un appui considérable de la part de quiconque croit à l'autorégulation par opposition à la législation ou aux stimulants économiques comme moyens de réduire les taux d'accidents et de maladie que l'on trouve dans les entreprises canadiennes. Malgré un internet plus marque pour l'établissement et le développement des comités paritaires de santé et de sécurité au travail, peu d'études ont été effectuées pour en apprécier l'efficacité. Cet article traite des principaux facteurs d'évaluation de ces comités. Des quelques travaux qu'on a réalisés sur le sujet et de leur examen, il est possible d'énumérer une série de mesures de la valeur de cette forme de participation des travailleurs. Les données accessibles en Alberta (enquêtes au moyen d'entrevues) et en Saskatchewan (résumés annuels tires des procès-verbaux des assemblées de comités) sont évaluées à la lumière de ces mesures de façon à répondre à la question : « Les comités paritaires de santé et de sécurité professionnelles sont- ils efficaces? » En se fondant sur des critères surs, nous croyons que l'enquête de l'Alberta et les statistiques tirées des procès-verbaux de la Saskatchewan fournissent la preuve certaine qu'ils sont efficaces. C'est par la diminution des blessures et des maladies que leur valeur se mesure le mieux. Cependant, celle-ci doit aussi reposer sur d'autres critères tels que leur influence sur les relations professionnelles et la prise de conscience qu'elle entraine tant chez les travailleurs que chez les employeurs de l'importance des programmes de santé et de sécurité par les diverses mesures qu'ils peuvent susciter. Bien qu'il soit encore trop tôt pour conclure que les comités paritaires de santé et de sécurité sont des instruments surs pour réduire les blessures et les maladies professionnelles, certains indices montrent que tel est le cas. Il est plus probable que l'impact de ces comités ressortira avec le temps et nous recommandons qu'une étude des variables macroéconomiques, associée à une analyse des procès-verbaux des comités et à l'utilisation de méthodes d'enquête par entrevues, serait la plus susceptible de répondre de façon concluante à la question de savoir si ces comités sont efficaces ou non. Nous avons de bonnes raisons d'être optimistes, parce que, en tant qu'expression de la maturité politique des entreprises canadiennes, ce type de comités paritaires a été accepte par la grande majorité des industries et des gouvernements au Canada comme moyen de répondre aux problèmes croissants de santé et de sécurité au travail. Leur acceptation par les travailleurs, les employeurs et les gouvernements devrait assurer leur développement et leur sécurité.

<p>In order to increase the workplace health and safety, the EU Directive 89/391/CEE and the Romanian law 319 of 2006 introduced the principle of the balanced participation of the employer and employees in health and safety committees. The findings of the in-depth interviews with members of two committees and employees from two Romanian companies show that the workplace health and safety committees with balanced participation of the employers and employees are organizations that do not respect the letter and the spirit of the EU and the Romanian laws. Moreover, workplace health and safety committees do not fit well with the employees and employers’ attitudes, values and knowledge. Thus, based on research findings, some recommendations can be developed so that these committees function according to regulations.</p>

Tuis article extends the existing documentation of interest group activities in the commit- tees of the German Bundestag for the 18th election period. Tue documentation goes beyond previous ones by including sub-committees and taking into account contacts between stakeholders and representatives also in regular committee meetings. While most figures structurally remain the same as in the 17th election period, changes can be identified in particular for committees whose responsibilities have changed. Tuus, established patterns of interest group representation may also change in the context of committee reorganization.

With the initiation in the late 1960s of the data and safety monitoring board or equivalently the data monitoring committee in randomized clinical trials came the need for interim statistical reports for these committees to review for study conduct and early evidence of harm or overwhelming evidence of benefit, perhaps leading to early trial termination. Initially, the statistical team was part of the data coordinating center for the trial. Later, starting in the early 1990s in many industry-sponsored trials, this statistical unit was separated organizationally from the team that collected and managed the data. This unit, often referred to as the statistical data analysis center, prepares reports for the data monitoring committee, which cover study conduct, data quality and completeness, primary and secondary outcomes, and safety measures by study arm in an unblinded fashion. The role of the statistical data analysis center is critical to any well-functioning data monitoring committee. With the proliferation of data monitoring committees has grown the need for many more well-trained and experienced statistical data analysis centers. In my experience, some such units perform their tasks extremely well but many do not. There is a tremendous need and opportunity to provide training for statistical data analysis centers, and what sponsors and data monitoring committees should expect from statistical data analysis centers.

A Work Environment Board was established to deal with all workplace health and safety issues within the Potash Corporation of Saskatchewan from 1978 to 1982. The Board was an experiment, established because of the observed deficiencies of the mandatory joint occupational health and safety committees that were legislated by the province in 1972. The administrators of the occupational health and safety program observed the problems faced by workers on these committees. An experiment was therefore established in one of the province's crown corporations that would transform the joint committee into a Work Environment Board with wider powers to deal with work environment matters within the corporation. In addition, a Work Environment Fund was established to enable the worker members on the Board to do their own research and to get the information they wanted. The Work Environment Board was frustrated by the fact that corporate leaders were not prepared to extend worker rights on the health and safety committees within the respective mines. Rather, they viewed health and safety reforms as part of an overall strategy of quality of work life. The social democratic government was not prepared to extend worker rights and to threaten management prerogatives. Now that there are three New Democratic Party (social democratic) governments in Canada, it appears that these governments are prepared to initiate technical improvements, but not the extension of worker rights in work environment matters.

Abstract Background: rVIII-SingleChain, a novel recombinant Factor VIII, has been designed as a B-domain truncated construct with a covalent bond between the heavy and light chain, aiming for a higher binding affinity to von Willebrand Factor. rVIII-SingleChain has a lower clearance, longer half-life and larger area under the curve compared to octocog alfa (Advate®). This sub-study of the AFFINITY program investigated the safety and efficacy of rVIII-SingleChain to control hemostasis in adult and adolescent patients (12 - 65 years of age) with severe Hemophilia A undergoing major surgery. rVIII-SingleChain was used either as continuous infusion or as a bolus injection. Methods: The study was approved by the relevant ethics committees and national authorities and conducted according to GCP and the Declaration of Helsinki. 13 patients underwent a total of 16 major surgical procedures (a surgical procedure that required general, spinal or regional anesthesia). Dosing was guided by the WFH recommendations. In 8 patients, rVIII-SingleChain was used as continuous infusion and in 8 patients rVIII-SingleChain was used as a bolus injection. Results: The following procedures were performed using continuous infusion: knee replacement (5), cholecystectomy, lengthening of the achilles tendon combined with surgical correction of the right toes, and open reduction and internal fixation of right ankle fracture. Furthermore, circumcision (3), extraction of wisdom teeth, abdominal hernia repair, elbow replacement, ankle arthroplasty, and hardware removal of the right ankle were performed after administering a bolus injection of rVIII-SingleChain. In the 8 procedures that were covered by bolus injection rVIII-SingleChain median pre- and intraoperative consumption was 79.2 IU/kg, and in the 8 procedures that were covered by continuous infusion, rVIII-SingleChain median pre- and intraoperative consumption was 92.5 IU/kg. Investigators rated the efficacy of rVIII-SingleChain during surgery as excellent (defined as hemostasis not clinically significant different from normal) in all cases but one (knee replacement under continuous infusion), in which it was rated as good (defined as hemostasis normal or mildly abnormal in terms of quantity and/or quality e.g., slight oozing). After the procedure, patients returned to routine treatment after a median of 9 days. No related AEs or SAEs were observed during the surgery period. Conclusion: rVIII-SingleChain provides very effective and safe control of hemostasis during a wide range of surgical procedures when dosed either by continuous infusion or by bolus injection. Consumption of factor on the day of surgery seems to be comparable in both treatment regimens. Disclosures Mahlangu: NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baker:Daiichi Sankyo: Research Funding; CSL Behring: Research Funding; Portola Pharmaceuticals: Research Funding; Astellas: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: conference travel support, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support , Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Other: conference travel support. Leissinger:Biogen: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Santagostino:Pfizer: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Biotest: Speakers Bureau; Octapharma: Speakers Bureau; Kedrion: Speakers Bureau; Biogen/Sobi: Membership on an entity's Board of Directors or advisory committees. Bensen-Kennedy:CSL Behring: Employment. St. Ledger:CSL Behring: Employment. Veldman:CSL Behring: Employment. Pabinger:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Pacritinib, a novel JAK2/IRAK1 inhibitor, demonstrated clinically significant activity in spleen volume and symptom reduction in patients with advanced cytopenic myelofibrosis (MF), including those with severe thrombocytopenia (platelet [PLT] count &lt;50 × 10 9/L), in phase 2 and 3 clinical studies. Cytopenic MF, characterized by thrombocytopenia, anemia, and transfusion requirements, is associated with poor prognosis and shortened survival. Patients with cytopenic MF represent a challenging population, as therapeutic options are limited or must be given at reduced doses, which impairs efficacy. Pacritinib, unlike JAK1/2 inhibitors, has demonstrated clinical benefit at the recommended full dose of 200 mg twice daily (BID) in patients with cytopenias in the phase 2 dose-finding PAC203 and phase 3 PERSIST-2 studies. To characterize the safety profile of pacritinib in patients with cytopenic MF at the full-dose of 200 mg BID, we performed a retrospective analysis of the data from these studies. Methods: Patients with baseline PLT &lt;50 x 10 9/L treated with pacritinib 200 mg BID in PERSIST-2 and PAC203 or best available therapy (BAT) in PERSIST-2 were included as the target patient population in this analysis. In PERSIST-2, patients were randomized 1:1:1 to pacritinib 200 mg BID, pacritinib 400 mg once daily (QD), or BAT, including ruxolitinib (40%) or watch and wait (31%); patients could be either JAK inhibitor-naive or have had prior exposure. PAC203 included patients who were intolerant of and/or resistant to ruxolitinib and randomized 1:1:1 to pacritinib 100 mg QD, 100 mg BID, or 200 mg BID; enhanced safety measures were incorporated in the study design to reduce the risk of high-grade bleeding and cardiac events. Adverse events (AEs) were classified and graded according to the Common Terminology Criteria for AE. Standardized MedDRA Query (SMQ) was used to assess bleeding and cardiac events. Major cardiac events were analyzed using major adverse cardiovascular events (MACE) classification. Results: A total of 71 patients were analyzed as the pooled pacritinib 200 mg BID group (n=47 in PERSIST-2; n=24 in PAC203) and 42 patients in the BAT group. In addition to having severe thrombocytopenia, patients in the pooled pacritinib group had significant anemia, with median hemoglobin 8.6 g/dL, and 34% required red blood cell transfusion at baseline (Table 1). Sustained dose intensity was observed for the pacritinib group, with median dose of 400 mg/day in PERSIST-2 and 396 mg/day in PAC203. In the BAT subgroup from PERSIST-2, among the patients who received ruxolitinib the median post-titration dose was 10 mg/day. A total of 44% of patients treated with pacritinib and 21% treated with BAT had drug exposure ≥6 months. All-grade treatment-emergent adverse events (TEAEs) and those leading to study drug discontinuation were observed at similar rates in the pooled pacritinib and BAT groups. The patients in the pooled pacritinib group had a higher incidence of grade ≥3 and treatment-emergent serious AEs compared to those on BAT, which included patients on supportive care strategies. In the pooled pacritinib group, all-grade TEAEs were mostly driven by thrombocytopenia (32%) and gastrointestinal events, which included low grade nausea (30%) and diarrhea ([41%], which was manageable with over-the-counter antidiarrheals and resolved without leading to drug discontinuation). Rates of other commonly reported AEs in both trials were lower in the pooled pacritinib group compared to BAT, including epistaxis and peripheral edema. Fewer patients experienced fatal TEAEs in the pooled pacritinib group (Table 2). The incidence of serious and grade ≥3 bleeding AE was lower with pacritinib 200 mg BID in PAC203 than those reported with pacritinib 200 mg BID or BAT in PERSIST-2, likely attributable to the additional safety measures in PAC203 (Table 2). Incidence of cardiac events of any grade and those grade ≥3 were lower in the pooled pacritinib group compared to BAT. No patients in the pooled pacritinib group and 2 in the BAT group (1 fatal) had a MACE event (Table 2). Conclusion: In this analysis of patients with cytopenic MF who have severe thrombocytopenia, the safety profile of pacritinib 200 mg BID was comparable to BAT. This analysis suggests that pacritinib 200 mg BID may represent the first fully-dosed therapeutic option for this challenging patient population. Figure 1 Figure 1. Disclosures Mascarenhas: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding; Geron: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Geron: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Galecto: Consultancy; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison: Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau. Gerds: Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; PharmaEssentia Corporation: Consultancy; Novartis: Consultancy. Rampal: Incyte: Consultancy, Research Funding; BMS/Celgene: Consultancy; Stemline: Consultancy, Research Funding; Kartos: Consultancy; Constellation: Research Funding; Jazz Pharmaceuticals: Consultancy; Blueprint: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Pharmaessentia: Consultancy; Sierra Oncology: Consultancy; Memorial Sloan Kettering: Current Employment; Disc Medicine: Consultancy. Buckley: CTI Biopharm: Current Employment. Craig: CTI BioPharma: Current Employment. Smith: CTI: Current Employment. Volpone: CTI: Current Employment. Roman-Torres: CTI Biopharm: Current Employment. Mesa: Samus: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Pharma: Consultancy; CTI: Research Funding; CTI: Research Funding; Sierra Oncology: Consultancy, Research Funding; Abbvie: Research Funding; Promedior: Research Funding; AOP: Consultancy; La Jolla Pharma: Consultancy; Genentech: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Celgene: Research Funding.

Institutional ethics committees remain largely absent from the literature on error reduction and patient safety. This paper attempts to fill the gap. Healthcare professionals are on the front lines in the defense against medical error, but the changes that are needed to reduce medical errors and enhance patient safety are cultural and systemic in nature. As noted in the Hastings Centers recent report, Promoting Patient Safety, the occurrence of medical error involves a complex web of multiple factors. Human misstep is certainly one such factor, but not the only one. In this paper, I build on the Hasting Centers report on patient safety (HCR) in arguing that institutional ethics committees ought to play an integral role in the transformation of a culture of blame to a culture of safety in healthcare delivery.

Abstract BACKGROUND: Despite improvements in the treatment of "unfit or older" AML patients with the combination of azacitidine (AZA) and venetoclax (VEN), long-term survival for these patients remains poor. Additions to this new regimen may further improve patient outcomes. Overexpression of CD123, the alpha subunit of the IL-3 receptor, is seen in AML blasts. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprised of a high-affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. Preclinical data have demonstrated synergy between IMGN632 and AZA and/or VEN, including overcoming AZA/VEN resistance in murine AML models (Kuruvilla ASH 2020), supporting the clinical exploration of these combinations. Doublets of IMGN632 with both AZA and VEN were studied in AML patients and supported testing of the triplet of IMGN632, AZA, and VEN. Here we report the initial safety and anti-leukemia activity findings from this novel triplet. METHODS: This Phase 1b/2 study was designed to determine the safety, tolerability, and preliminary anti-leukemic activity of IMGN632 combined with AZA and VEN in patients with CD123-positive AML. To date, the triplet combination escalation consists of 5 cohorts of IMGN632 plus AZA and VEN, each agent designated by "C" for IMGN632 dose in mcg/kg, "A" for AZA dose in mg/m2 x7 days, or "V" for VEN # of days at 400mg QD. Four cohorts dosed IMGN632 on Day 7 of each cycle (C15A50V8, C15A50V14, C15A75V21, C45A50V8), and one cohort dosed IMGN632 on Day 1 of each cycle (Day 1 C15A50V14). Responses are determined using modified ELN criteria with a 14-day count recovery window. RESULTS: At the time of this analysis, preliminary safety data are available for 35 relapsed or refractory (R/R) AML patients. The median age was 69y, 23% had secondary AML, 86% received prior intensive therapies, 37% that were refractory to first line therapy, and 51% had received prior VEN. Twenty-three percent of patients had FLT3 mutations. The toxicity profile was manageable in this R/R AML population with multiple prior therapies. The most common treatment emergent adverse events (TEAE) all grades [grade 3+ events] seen in &gt;20% of patients were infusion-related reactions (IRR, 37% [3%]), febrile neutropenia (26% [23%]), hypophosphatemia (26% [3%]), dyspnea (26% [6%]), pneumonia (20% [14%]), and fatigue (20% [0%]). One patient in the Day 1 C15A50V14 cohort discontinued IMGN632 due to a TEAE (DLT IRR, resolved). Cytopenias and infections were consistent with those observed with the AZA+VEN regimen in this R/R population. No TLS, VOD, capillary leak or cytokine release were observed. 30-day mortality was 0%. Efficacy was seen across all cohorts/doses and schedules (efficacy evaluable population, n=29). The objective response rate (ORR) was 55% with a composite complete remission (CCR) rate of 31% (1 CR, 4 CRh, 2 CRp, 2 CRi). Higher intensity cohorts (IMGN632 dose 45 mcg/kg or 14-21 days of VEN) on the Day 7 schedule (n=20) were associated with higher response rates: ORR 75%, CCR rate 40% (Figure 1). At these higher intensity cohorts, in the VEN naïve subset (n=10), ORR/CCR rates were 100%/60%, respectively. Significant activity was also seen in the FLT3 mutant subset (n=7), with ORR/CCR rates of 100%/71%. CONCLUSION: With a manageable safety profile in this R/R AML population, the novel IMGN632 triplet demonstrated compelling anti-leukemia activity. Ongoing escalation cohorts aim to optimize safety and efficacy of the triplet therapy. Expansion proof-of-concept cohorts are planned in both relapsed and frontline AML patients (NCT04086264). Updated safety, efficacy, and PK data will be presented. Figure 1 Figure 1. Disclosures Daver: Trillium: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Hanmi: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Aribi: Seagen: Consultancy. Montesinos: Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Roboz: Astex: Consultancy; Jazz: Consultancy; Glaxo SmithKline: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Astellas: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Jasper Therapeutics: Consultancy; Celgene: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Wang: Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Walter: Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Current equity holder in publicly-traded company; Aptevo Therapeutics, Inc.: Consultancy, Research Funding; Arog Pharmaceuticals, Inc.: Research Funding; Astellas Pharma US, Inc.: Consultancy; BioLineRx, Ltd.: Consultancy, Research Funding; Boston Biomedical, Inc.: Consultancy; Bristol Myers Squibb, Inc.: Consultancy; Celgene, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy; GlaxoSmithKline, Inc.: Consultancy; ImmunoGen, Inc.: Research Funding; Janssen Global Services, LLC: Consultancy; Janssen Research & Development, Inc.: Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy, Research Funding; Kite Pharma, Inc.: Consultancy; Kronos Bio, Inc.: Consultancy; Kura Oncology, Inc.: Research Funding; Macrogenics, Inc.: Research Funding; New Link Genetics: Consultancy; Pfizer, Inc.: Consultancy, Research Funding; Race Oncology Ltd.: Consultancy; Selvita: Research Funding; Stemline Therapeutics, Inc.: Research Funding. Jeyakumar: Jazz: Research Funding; Pfizer: Research Funding. DeAngelo: Abbvie: Research Funding; Blueprint Medicines Corporation: Consultancy; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Agios: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Shire: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy. Erba: Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Agios, Amgen, Astellas Pharma, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Covance (AbbVie): Other: Independent Review Committee ; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, and PTC: Research Funding. Advani: Abbvie: Research Funding; Immunogen: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; OBI: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinelli: Celgene /BMS: Consultancy, Speakers Bureau; Stemline Therapeutics: Consultancy; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy; Daichii Sankyo: Consultancy; Incyte: Consultancy; Astellas: Consultancy, Speakers Bureau. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Altman: Biosight: Membership on an entity's Board of Directors or advisory committees, Other: reimbursement for travel, Research Funding; ImmunoGen: Research Funding; Kartos Therapeutics: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Glycomimetics: Other: data monitoring committee; Loxo: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Honoraria, Research Funding; Aptos: Research Funding; Aprea: Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; ALX Oncology Inc.: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees. de la Fuente: Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding; BMS: Consultancy, Speakers Bureau. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Boissel: PFIZER: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; JAZZ Pharma: Honoraria, Research Funding. Recher: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Incyte: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Konopleva: Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Sallman: Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Kantarjian: KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; NOVA Research: Honoraria; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; Astellas Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Precision Biosciences: Honoraria. Malcolm: Immunogen: Current Employment. Zweidler-McKay: ImmunoGen: Current Employment. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who fail multi-agent chemoimmunotherapy have a poor prognosis and a need for more treatment options. Loncastuximab tesirine (Lonca) comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. We present updated results from a phase 2 study of Lonca in patients with R/R DLBCL who had failed established therapies, including analysis of response in high-risk DLBCL subgroups. Methods: Patients aged ≥18 years with R/R DLBCL who had failed ≥2 prior therapies were enrolled in this single-arm open-label phase 2 study (NCT03589469). Overall response rate (ORR) was assessed by independent reviewer according to the Lugano response criteria and duration of response (DoR) was defined as the time from earliest date of first response until the first date of either disease progression or death due to any cause. Pre-specified analyses of ORR and DoR by demographic and clinical characteristics were performed. Treatment-emergent adverse events (TEAEs) were reported for the all-treated population and by age group. Results: In this study, 145 patients with DLBCL received Lonca (mean 4.3 cycles [range: 1-15]) and were evaluable for safety and efficacy. As of data cutoff (April 6, 2020), follow-up was ≥6 months since first dose. The ORR was 48.3%, and complete response rate (CRR) was 24.1%. Median DoR (mDoR) for the 70 responders was 10.3 months. For patients with a CR, mDoR was 13.4 months (Figure 1). Most patients responded after 2 treatment cycles; median time to first response was 41.0 days. Responses, including CRs, were observed in several subgroups with higher-risk characteristics (Figure 2). ORR was 44.8% in patients with transformed disease, 45.8% in patients aged 65-74 years, and 52.4% in patients aged ≥75 years. For patients with double- or triple-hit DLBCL, ORR was 33.3% (notably all CRs). Patients who were refractory (no response) to first-line therapy, most recent therapy, or any prior therapy had ORRs of 37.9%, 36.9%, and 36.0%, respectively. Patients who had received a prior stem cell transplant (SCT) had a notable ORR of 58.3%. Lonca was also effective in patients who had received prior CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy (ORR 46.2%). Durable responses were noted in patients with high-risk characteristics. mDoR was not reached for patients with transformed disease. Older patients had a longer mDoR than younger patients (&lt;65 years: 9.6 months; 65-74 years: 10.3 months; ≥75 years: 13.4 months). Patients with double- or triple-hit DLBCL had a mDoR of 13.4 months. mDoR was comparable for patients who were refractory to first-line therapy, most recent therapy, or any prior therapy (each 9.6 months) and for those who relapsed after first-line therapy, most recent therapy, or any prior therapy (each 10.3 months). Following Lonca treatment, 15 patients received CD19-directed CAR-T therapy with an investigator-assessed ORR of 46.7% (6 CR; 1 partial response), and 9 patients proceeded to SCT as consolidation after responding to Lonca. Overall, 143 (98.6%) patients had ≥1 TEAE and 105 (72.4%) patients had grade ≥3 TEAEs. The most common (≥25%) all-grade TEAEs were gamma-glutamyltransferase (GGT) increased (40.7%), neutropenia (39.3%), thrombocytopenia (33.1%), fatigue (27.6%), and anemia (26.2%). The most common (≥10%) grade ≥3 TEAEs were neutropenia (25.5%), thrombocytopenia (17.9%), GGT increased (16.6%), and anemia (10.3%). Treatment-related TEAEs leading to treatment discontinuation occurred in 24 patients (16.6%), most commonly GGT increased (14 patients; 9.7%). No increase in toxicity was seen in patients aged ≥65 years compared with younger patients. Conclusions: Lonca had substantial single-agent antitumor activity in patients with R/R DLBCL. No new safety concerns were identified and no increase in toxicity was observed for patients aged ≥65 years. Encouraging and durable responses were observed in high-risk patient groups, including double- or triple-hit, transformed or refractory DLBCL, and notably in those who had progressed after prior CAR-T cell therapy. In addition, investigator-reported ORR indicates that many patients also respond to CAR-T therapy given after Lonca. Updated DoR data will be presented at the meeting. Funding: This study is sponsored by ADC Therapeutics SA; clinicaltrials.gov/ct2/show/NCT03589469. Disclosures Caimi: Celgene: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Puma Biotechnology: Other: Family member; Foundation Medicine: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member. Ardeshna:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi, Genzyme, AstraZeneca: Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; University College London (UCL)/UCL Hospitals (UCLH) Biomedical Research Unit: Other: Supported by this organisation; Beigene: Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Sanofi Genzyme, AstraZeneca: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kahl:Roche Laboratories Inc: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC: Consultancy. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stathis:Member of the steering committee of the trial of this abstract: Other; Loxo: Honoraria, Other, Research Funding; Cellestia: Research Funding; PharmaMar: Other: Travel Grant; Abbvie: Other: Travel Grant; ADC Therapeutcis: Other, Research Funding; MEI Pharma: Other, Research Funding; Novartis: Other, Research Funding; Bayer: Other, Research Funding; Merck: Other, Research Funding; Roche: Other, Research Funding; Pfizer: Other, Research Funding. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Qin:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. He:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy.

A national peace committee is a multi-stakeholder body mandated to implement key peacebuilding objectives, and coordinate a multi-level network of peace committees called an infrastructure for peace. Based on 10 case studies, the article explores the importance of political legitimacy for the success of NPCs and analyses, in particular, the contribution of their mandate, role clarity, composition and competence.

144 Background: Enhancing patient safety can prevent unintended outcomes arising from defects in healthcare delivery systems. The Hematology/Oncology Patient Safety Committee (HOPSC) at Beth Israel Deaconess Medical Center (BIDMC) is a multidisciplinary team of healthcare providers that meets monthly to review inpatient and outpatient adverse events, near misses, and medical errors that impact patient safety. Methods: Our aim was to quantify and qualify the cases that the HOPSC has reviewed from 2012-2013. In order to identify trends in event reporting, we reviewed the number of events reported to the HOPSC in both the inpatient and outpatient settings. We further subdivided events into two categories: medication-related and non-medication related. Additionally, we delineated which healthcare provider initiated the reporting of each event. Results: Over the two-year period, a total number of 1,061 events were reported to the HOPSC. Of these, 259 were medication-related events. Of the events reported, 40 were by a physician/NP and 1,021 were by a nurse. There was a discrepancy in the type of event reported (24.4% medication vs. 75.6% non-medication related) as well as in the type of reporter (3.8% physician/NP vs. 96.2% nurse). Of all the events reported, 8 were escalated to the Department of Medicine Peer Review Committee. Conclusions: Through review of healthcare provider event reports, the HOPSC has identified several types of adverse events and near misses in the Hematology/Oncology division at BIDMC. The events are mostly reported by inpatient nurses and are primarily medication-related. Given this skewed reporting pattern, we will investigate the reasons why reporting by physicians, especially in the outpatient setting, is limited. Our reported outline of the HOPSC operations may also guide oncology practices elsewhere in their own development of patient safety peer review committees. [Table: see text]

Abstract Introduction: The interleukin-3 receptor alpha chain (CD123) is a cell-surface target aberrantly expressed on various myeloid neoplasms including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). Tagraxofusp (TAG, SL-401), a first-in-class CD123-targeted therapy, is the only treatment approved by the FDA and EMA for patients (pts) with BPDCN. It has also been investigated in phase 1/2 clinical trials for AML (including pts with minimal residual disease [MRD]), CMML, and MF. We report the aggregated safety data of TAG monotherapy from trials in BPDCN, AML, CMML, and MF. Methods: An integrated safety analysis was performed for pts who received TAG monotherapy in three phase 1/2, multicenter clinical studies: Study 0114 (NCT02113982; BPDCN/AML), Study 0214 (NCT02270463; AML with/without MRD), and Study 0314 (NCT02268253; CMML/MF; Table 1). Pts received the recommended phase 2 dose of 12 mcg/kg/day (d) IV on d1-3 (MF and CMML) or d1-5 (BPDCN and AML) and were analyzed for incidence and timing of treatment-related adverse events (TRAEs), AEs of interest, and discontinuations. Safety data for TAG monotherapy, reported as individual case study reports (ICSRs) postapproval (US) and from an early access program (EAP; EU) are also presented. Results: In total, 201 pts receiving TAG (12 mcg/kg/d) in a clinical trial setting were included: BPDCN, n=86; AML, n=36; AML with/without MRD, n=10; CMML, n=33; MF, n=36. As of Jul 2021, 11 (6%) pts discontinued TAG due to any-grade (Gr) TRAE. Most common TRAEs (any-Gr) are shown in Table 2 and included hypoalbuminemia (41%), increased alanine aminotransferase (ALT; 40%), increased aspartate aminotransferase (AST; 39%), and thrombocytopenia (26%). The most common Gr ≥3 TRAEs were thrombocytopenia (n=41; 20%), increased AST (n=40; 20%), and increased ALT (n=35; 17%). Tumor lysis syndrome occurred in 5% of pts and 1.5% had infusion-related reactions. Any-Gr and Gr ≥3 hematologic TRAEs are presented in Table 3. Most common was thrombocytopenia. All TRAEs were transient in nature; prolonged bone marrow suppression was not observed. Overall, 23% (47/201) of pts experienced ≥1 treatment-related serious AE. Onset of most TRAEs, irrespective of Gr, commonly occurred in cycle 1 and resolved by cycle 2. Although the number of pts in cycles ≥2 was lower than in cycle 1, the incidence rates of common TRAEs also substantially decreased in subsequent cycles. Capillary leak syndrome (CLS) occurred in 17% of the overall 201 pts. The majority of all CLS events were nonsevere, Gr ≤2 (n=22; 63%); also reported were Gr 3, n=10 (29%); Gr 4, n=3 (9%), and 2 pts experienced a Gr 5 event. Onset of CLS was usually within the first week of cycle 1 (median time to onset [range], d: 5.5 [1-51]) and resolved quickly (median time to resolution [range], d: 5.0 [2-69]); no pts experienced the first onset after cycle 2. Of the 15 pts who resumed treatment after an initial CLS event, only 1 pt experienced a recurrence. The most common AEs reported as ICSRs postapproval and from an EAP (December 2018 to June 2021) were CLS, blood albumin decreased, thrombocytopenia, pyrexia, and hepatic enzyme increased. No new safety signals that would alter the safety profile were observed. Conclusions: This integrated analysis represents the largest collection of safety data (N=201) following treatment with TAG monotherapy. TAG has an established and manageable safety profile, with the vast majority of AEs reported as transient and decreasing in frequency/severity with increasing cycles. CLS was reported in 17% of pts; onset was usually within cycle 1, resolved quickly (median time to resolution: 5.0 d) by early intervention measures including holding treatment, and no pts experienced first onset after cycle 2. Risk-minimization guidelines for CLS were developed and implemented during clinical trials and incorporated into prescribing information. No myelosuppression or cumulative toxicity was observed over multiple treatment cycles. The safety profile observed postapproval and in the EAP was consistent with the clinical trial data reported, reflecting successful adoption of risk-management strategies in real-world practice. These data confirm the favorable benefit-risk profile of TAG monotherapy has been maintained in the 3 years following US approval. Figure 1 Figure 1. Disclosures Pemmaraju: ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Pacylex Pharmaceuticals: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; Celgene Corporation: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Samus: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; DAVA Oncology: Consultancy; Plexxicon: Other, Research Funding; Roche Diagnostics: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ImmunoGen, Inc: Consultancy. Kantarjian: NOVA Research: Honoraria; Aptitude Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Jazz: Research Funding; Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Lane: N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; AbbVie: Research Funding. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; AROG: Other; Amgen: Other: personal fee; Bayer: Consultancy, Honoraria; Kite: Other: personal fee; Mustang: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Other: personal fee; Gilead: Other: personal fee; Jazz: Other: personal fee; Pharmacyclics: Other. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Gupta: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: Sangamo: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; FujiFilm: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Celator: Research Funding; Actuate: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Trovagene: Research Funding; Deciphera: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding; Takeda: Research Funding; Geron: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Tolero: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Samus: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Ariad: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Foran: trillium: Research Funding; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; OncLive: Honoraria; servier: Honoraria; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; abbvie: Research Funding; certara: Honoraria; bms: Honoraria; pfizer: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; taiho: Honoraria; syros: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Walter: Macrogenics: Consultancy, Research Funding; Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Sieminski: Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Konopleva: Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding.

Abstract Background: rVIII-SingleChain, a novel recombinant Factor VIII (rFVIII), has been designed as a B-domain truncated construct with a covalent bound between the heavy and light chain, aiming for a higher binding affinity to von Willebrand Factor (vWF). A currently ongoing study is investigating the pharmacokinetics, efficacy and safety of rVIII-SingleChain in children < 12 years of age with severe hemophilia A. Here, we report final PK and interim safety data for this fully enrolled but ongoing study. Final efficacy will be available for presentation. Methods: The study has been approved by the relevant Ethics committee and national authorities and is conducted according to GCP and the Declaration of Helsinki. A total of 84 subjects have been enrolled into the study, 35 of them in the 0 to <6 years age group and 49 in the 6 to <12 years age group. PK samples of rVIII-SingleChain were collected prior to infusion (pre-dose), 1, 4 to 6, 10, 24, and 48 hours post-infusion. Plasma FVIII activity was measured in the blood samples using the chromogenic substrate assay. Results: The PK results reported in the younger children (0-<6 years, n=20) were 10.4 h for t1/2, 5.07 mL/h/kg for CL, 12.4 h for MRT and 1077 IU*h/dL for AUCinf. In the older children (6-<12 years, n=19), they were 10.2 h for t1/2, 4.63 mL/h/kg for CL, 12.3 h for MRT and 1167 IU*h/dL for AUCinf. At the time of data cut, the study accumulated a total of 3651 exposure days (EDs) with 30 patients reaching > 50 EDs and 6 patients reaching >100EDs. No patient developed an inhibitor after exposure to rVIII-SingleChain. The rate of non-inhibitory anti-drug antibody formation was in line with recently published trials investigating novel rFVIII products. The most commonly observed AEs were nasopharyngitis and rhinitis. A total of 10 SAEs were reported in 7 patients the study so far, of which none was judged to be related by the investigators. Conclusion: The increased binding of rVIII-SingleChain to vWF translates into favorable pharmacokinetics without the need for glycopegylation or fusion to antibody fragments. Expectedly, mean t1/2 was shorter and mean CL greater in children when compared to adults and adolescents. rVIII-SingleChain demonstrated a very positive safety profile in this clinical study in children aged 0 to 12 years with severe hemophilia A. Disclosures Bensen-Kennedy: CSL Behring: Employment. St. Ledger:CSL Behring: Employment. Limsakun:CSL Behring: Employment. Veldman:CSL Behring: Employment. Pabinger:Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

BackgroundMedical record review (MRR) is used to assess the quality and safety in hospitals. It is increasingly used to compare institutions. Therefore, the external reproducibility should be high. In the current study, we evaluated this external reproducibility for the assessment of an adverse event (AE) in a sample of records from two university medical centres in the Netherlands, using the same review method.MethodsFrom both hospitals, 40 medical records were randomly chosen from patient files of deceased patients that had been evaluated in the preceding years by the internal review committees. After reviewing by the external committees, we assessed the overall and kappa agreement by comparing the results of both review rounds (once by the own internal committee and once by the external committee). This was calculated for the presence of an AE, preventability and contribution to death.ResultsKappa for the presence of AEs was moderate (k=0.47). For preventability, the agreement was fair (k=0.39) and poor for contribution to death (k=−0.109).ConclusionWe still believe that MRR is suitable for the detection of general issues concerning patient safety. However, based on the outcomes of this study, we would advise to be careful when using MRR for benchmarking.

This study covers the subject matter of bank accounts of campaign committees, including the ones taking part in the local government elections of 2018. It was also the author’s intention to discuss the background of the subject matter, which is why the presented discussion of the legislative framework refers also to bank accounts in general. Such an approach allows to refer the conclusions drawn to campaign committees taking part in other elections. Using the formal dogmatic method, the Author discusses the legal grounds for establishing cooperation between a bank and a customer (as parties to a bank account contract) and, then, between a bank and a campaign committee (as a specific customer type), obligations of the parties to that relationship and the bank’s obligations under other provisions performed in relation to campaign committees and bank accounts maintained for such campaign committees, including in particular in the area of counteracting money laundering and terrorist financing, and their impact on the performance of supervisory obligations and safety of the economic system.

Abstract Background: Treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. Methods: We retrospectively included SVT patients treated with VKAs and followed by 37 Italian Anticoagulation Clinics until June 2013. All documented bleeding and thrombotic events were reviewed by a Central Independent Adjudication Committee. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. Results: 375 patients with SVT on VKA treatment were included (median age 53 years; 54.7% males). The most common risk factors were: hematological diseases (21.6%), hepatic cirrhosis (15.2%), solid cancer (10.7%), recent abdominal surgery (8.0%) and intra-abdominal inflammation or infection (6.7%); in 37.1% SVT was unprovoked. The therapeutic INR target range was 2.0-3.0 in 353 patients (94.1%). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% CI, 0.75-2.06) per 100 patient-years. All bleeding patients were receiving warfarin with INR target range 2.0-3.0 and almost two thirds of bleeding complications occurred with therapeutic INR. One MB was fatal, corresponding to a case-fatality rate of 6.7%. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, adjusted for age and sex and stratified by Center, the presence of esophageal varices emerged as independent predictor of MB (HR 4.9; 95% CI, 1.4-17.1), while inflammatory bowel diseases were borderline statistically significant (HR 15.2; 95% CI, 0.99-233.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years, including 9 venous thrombosis and 7 arterial thrombosis. The mortality rate was 0.83 (95% CI, 0.45-1.54) per 100 patient-years. Conclusions: In designated SVT patients, oral anticoagulant treatment was safe, with a reported incidence of major bleeding less than 2% per year and a reasonable case-fatality rate. It is therefore of utmost importance to accurately select which SVT patients are suitable to be prescribed with VKAs. Disclosures Ageno: Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; STAGO: Honoraria. Rodeghiero:GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Suppremol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599. Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04). Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. Disclosures Rodríguez: PharmaMar: Employment. Ravandi:Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver:Sunesis: Consultancy; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Novartis: Research Funding; Otsuka: Consultancy. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti:Celgene Corporation: Other: Research funding to the institution. Martinez:PharmaMar: Employment. Siguero:PharmaMar: Employment. Al-Kali:Novartis: Research Funding.

ABSTRACT The Port of New York and New Jersey is a dynamic port boasting the United States' third largest container port. The 30 billion gallons of petroleum or petroleum products delivered to or originating from the port make it the largest petroleum port in the country, and the 50 million passengers transported annually on New York's waters by public and private ferries play a significant role within a finite system. Concomitant with increased waterway usage, there also have been changes in the desires of the public and governmental agencies for greater environmental protection, enhanced safety, public access to the waterfront, passenger and cargo security, and stakeholder coordination. The old stepwise incremental issue approach is too narrow to be efficient or effective in meeting these public demands. The port has been moving from a discreet modal analysis methodology, to an integrated systems-based approach in the form of a Harbor Safety Committee (HSC). A systems-based approach, involving multiple stakeholders, allows for inclusive and combine multiple economic, environmental, and social considerations in analyses to optimize and improve waterways system performance—from both safety and economic perspectives. HSCs also are playing an increasing role in identifying and mitigating risks resulting from increased waterways usage. New York's HSC is comprised of more than 60 firms, organizations and individuals, all having a vested interest in the port complex and the interaction between the different waterways users.

Background/aims: Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations (‘Trial Management Group’) and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, (‘Trial Steering Committee’), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee’s remit and operation and to potentially increase its usage. Methods: We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom–registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs. Results: In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a ‘steering’ committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan. Conclusion: A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption.