Safety and Efficacy of Tenalisib Given in Combination with Romidepsin in Patients with Relapsed/Refractory T-Cell Lymphoma: Final Results from a Phase I/II Open Label Multi-Center Study

Background: Tenalisib (RP6530), a highly selective PI3K δ/γ and SIK3 inhibitor has shown promising activity as a single agent in T Cell lymphoma (TCL) and a differentiated safety profile (Huen A et al., Cancers,2020). In vitro studies in TCL cell lines showed synergistic activity when tenalisib was combined with romidepsin. A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics, and efficacy in patients with relapsed/refractory (R/R) TCL peripheral (PTCL) and cutaneous T cell lymphoma (CTCL) (NCT03770000). Methods: This was a multi-center, open label study. We performed a Phase I, 3+3 dose escalation study to determine the MTD/recommended Phase II dose (RP2D), and a dose expansion study in both the subtypes separately (PTCL and CTCL). Patients received tenalisib at doses ranging from 400-800 mg BID (fasting), orally in combination with romidepsin at doses ranging from 12-14 mg/m 2, intravenously, given on Days 1,8 and 15 of a 28-day cycle. Results: Thirty-three patients (16 PTCL and 17 CTCL) who received more than 1 prior therapy were enrolled in the study; 9 in dose escalation and 24 in dose expansion. Of the 33 patients, 64% were refractory to their last therapy. The median number of prior therapies was 3. Most patients (67%) had stage III/IV disease at time of enrolment. No dose limiting toxicity (DLT) was reported during dose escalation; tenalisib 800 mg BID with romidepsin 14 mg/m 2 (given on Days 1, 8, and 15) was chosen as the RP2D. The most frequent treatment emergent adverse events (TEAEs) were nausea (All: 73% and ≥G3:0%), thrombocytopenia (All:57% and ≥G3:21%), fatigue (All: 54% and ≥G3:6%), AST elevation (All:33% and ≥G3:6%) ALT elevation (All:27% and ≥G3:18%), neutropenia (All: 27% and ≥G3:15%), vomiting (All:27% and ≥G3:0%), decreased appetite (All: 27% and ≥G3:0%). There were no unexpected TEAEs. Among CTCL patients, five related TEAEs led to drug discontinuation were sepsis, ALT elevation, GGT elevation, rash, and dysgeusia. None of the PTCL patients discontinued the study drug due to related TEAEs. Incidences of TEAEs leading to drug interruption (72%) and dose reduction (45%) of any the drugs in the combination were similar in PTCL and CTCL groups. Based on C max and AUC, dose proportional exposure of tenalisib was observed from doses 400-800 mg BID. Co-administration of romidepsin with tenalisib did not significantly alter the PK of either agent. Of the 33 patients enrolled, 27 (12 PTCL and 15 CTCL) who received at least 1 dose of study drug and provided at least 1 post-baseline efficacy assessment were considered evaluable for efficacy as per protocol. The overall response rate (ORR) was of 63%; 7 (26%) patients achieved CR and 10 (37%) patients had PR (Table 1). The median duration of response (DoR) was 5.03 months (range: 2.16 months-Not Reached). In twelve evaluable PTCL patients, the ORR was 75% with 6 CR (50%) and 3 PR (25%). Among 15 evaluable CTCL patients, 8 responded with an ORR of 53.3%, 1 CR (6.7%) and 7 PR (46.7%). The median DoR was 5.03 (range: 2.16 months-Not Reached) for PTCL and 3.8 months (1.9-18.86) for CTCL. Three of the six (50%) PTCL patients with CR were bridged to transplant. Six patients who benefitted with the treatment and completed the protocol were enrolled in an open-label compassionate medication study after Cycle 7 and are being followed up. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising anti-tumor activity in patients with R/R TCL. Based on these encouraging results, further development of this combination in PTCL patients in being planned. Figure 1 Figure 1. Disclosures Huen: Rhizen: Research Funding; Elorac: Research Funding; Kyowa Kirin: Research Funding; Tillium: Research Funding; Innate: Research Funding; Galderma: Research Funding; Miragen: Research Funding. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Kuzel: Cardinal Health: Membership on an entity's Board of Directors or advisory committees; Exelixis: Membership on an entity's Board of Directors or advisory committees; Genomic Health: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme Genomic Health Tempus laboratories Bristol Meyers Squibb: Honoraria; Abbvie: Other; Curio Science: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen Corp: Membership on an entity's Board of Directors or advisory committees; CVS: Membership on an entity's Board of Directors or advisory committees; Tempus Laboratories: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data Monitoring Committee Membership; Amgen: Other: Data Monitoring Committee Membership; SeaGen: Other: Data Monitoring Committee Membership; Medpace: Other: Data Monitoring Committee Membership.

Four-Fold Increased Mortality from Sars-Cov-2 Infection in Patients with Hematologic Versus Non-Hematologic Malignancies Treated at the Largest Tertiary COVID-19 Center in Chicago/Rush University Medical Center (March 1, 2020-December 31,2020)

N.K.Y., P.C., & P.R.Y. contributed equally to this study Introduction: Many studies have concluded that active cancer patients infected with SARS-CoV-2 have a more complicated infection course and worse outcomes compared to the general patient population hospitalized with COVID-19. However, little evidence exists whether having a history of cancer plays a significant role in these observations. Patients with hematologic malignancy (HM) might have worse prognosis among all cancer patients but the reason remains unclear. Our objective is to evaluate outcomes and severity of COVID-19 in patients with Hematological Malignancy (HM) versus Solid-tumors (ST) in different clinical settings and also compare these outcomes within the group of patients with hematological malignancies. Methods: This retrospective study examines risk factors and outcomes of COVID-19 in patients with a history of cancer and laboratory-confirmed COVID-19 diagnosis between March 1 st, 2020, and December 31 st, 2020, at Rush University Medical Center, one of the largest COVID-19 tertiary care hospitals in Chicago. Baseline characteristics, malignancy type and types of cancer treatment within the last 30 days were recorded. Measures of COVID-19 severity included hospital admission versus outpatient care, use of oxygen, intensive care unit (ICU) admission, and mechanical ventilation. The primary outcome was death. Statistical analysis was conducted using optimal discriminant analysis, a non-parametric exact machine-learning algorithm which identifies the relationship between independent and dependent variables that maximizes model predictive accuracy adjusted to remove the effect of chance. Analysis was performed separately for each attribute using the entire sample ("training" analysis), then one-sample jackknife analysis was conducted to estimate cross-generalizability of findings using the model to classify an independent random sample. Results: 378 total patients with a history of cancer tested positive for COVID-19 within the time frame of the study. Of these, 294 (78%) patients had ST malignancy and 84 (22%) patients had HM. Characteristics and outcomes are summarized in Table 1. ST patients were marginally older than HM patients (p<0.025). A significantly greater proportion of HM patients were male (p<0.0023). HM and ST patients did not differ with respect to percentage receiving active cancer treatment (p<0.81). Compared to ST patients, more HM patients had received corticosteroids in the 30 days prior to COVID-19 diagnosis (p<0.017), had higher rates of hospitalization (p<0.0013) and ICU requirement (p<0.0001) with a significantly longer length of ICU stay (p<0.0036). Compared to ST patients, HM patients also required oxygen (p<0.002) and mechanical ventilation (p<0.0005) more often and had a 3.88-fold statistically higher death rate (OR 3.88 [95% CI 1.62-9.29] p<0.003). Patients with HM are categorized by disease subtype and summarized in Table 2. The case fatality rate from COVID-19 was 33.3% for patients with myeloproliferative neoplasms/myelodysplastic syndromes (MPN/MDS), 21.4% for patients with chronic lymphocytic leukemia (CLL), 13.6% for patients with non-Hodgkin lymphoma, 10.5% for patients with plasma cell neoplasms, and 4.5% for patients with acute leukemia. When looking at outcomes, CLL had the highest percentage of patients requiring hospital admission, oxygen, and ICU admission, and MPN/MDS had the highest percentage of patients requiring mechanical ventilation. Conclusions: Patients with hematologic malignancies had more severe COVID-19 illness and hospitalization rates and a 3.88-fold higher rate of death than patients with solid tumors. The comparable proportion of patients on anti-cancer therapy despite differences in survival suggests that being on anti-cancer therapy is less important than the underlying diagnosis of HM versus ST as a determinant of poor outcomes. Clinicians should closely monitor and initiate early COVID-19 treatments for all patients with HM and COVID-19. Because HM are highly heterogenous group of cancers, it is important to look at subtypes in greater detail. Numerous patient-level, disease-specific, and therapy-related factors may impact outcomes of COVID-19 among patients with HM, and we are currently analyzing additional data to better understand the factors which make this disease group more susceptible to severe infection. Figure 1 Figure 1. Disclosures Kuzel: Sanofi-Genzyme Genomic Health Tempus laboratories Bristol Meyers Squibb: Honoraria; Genomic Health: Membership on an entity's Board of Directors or advisory committees; Exelixis: Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other; Curio Science: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen Corp: Membership on an entity's Board of Directors or advisory committees; CVS: Membership on an entity's Board of Directors or advisory committees; Tempus Laboratories: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data Monitoring Committee Membership; Amgen: Other: Data Monitoring Committee Membership; SeaGen: Other: Data Monitoring Committee Membership; Medpace: Other: Data Monitoring Committee Membership.

Norway

In this chapter, we describe the institutional setting of parliamentary debate in Stortinget and identify correlates of speech participation, drawing on a dataset of more than a quarter of a million speeches from 1998 to 2016. The key correlate of speech participation is committee membership in the committee responsible for preparing the report for the topic under discussion. However, that is not the whole story. Party elites speak more than backbenchers. As speaking time is allocated proportional to party size, MPs from the smaller parties speak more often than their counterparts in the larger parties. While we uncover a gender difference in the overall allocation of speeches, this is only present amongst parties on the right of the political spectrum. We do not find a similar difference in length of speech or allocation of speeches amongst members within the same committee. Hence, we ascribe the gender difference in speeches to gender differences in committee composition.

INFLUENCE OF TENDERING PROCESSES ON THE PERFORMANCE OF NATIONAL GOVERNMENT CONSTITUENCY DEVELOPMENT FUND PROJECTS A CASE STUDY OF BOMET EAST CONSTITUENCY, BOMET COUNTY, KENYA

Purpose: The purpose of the study was to examine the influence of tendering processes on the performance of National Government constituency development fund projects.Methodology: The study adopted a case study design to achieve in-depth understanding of the constituency while drawing inference on similar situations in other constituencies in Kenya. The study targeted 359 projects of various types across the constituency. However, for efficiency and accessibility, a sample of 60 projects were selected using stratified random sampling where the different categories of projects form the strata from which samples were selected. The study employed three tools to collect data; questionnaire, interviews and record analysis review. These tools were appropriate due to the nature of data which ranged from opinions, structured data and reports on project implementation. Interviews were conducted with sub-county based officers to get in- depth information on the challenges faced by NG-CDF projects particularly those that relate to procurement. The study adopted descriptive statistics to analyze data which is presented by use of bar graphs, pie charts and tables.Findings: The study established that, there is indeed a relationship between tendering processes and project performance; 47% of the projects under study that were initiated during period delayed due to factors associated with tendering processes; Similarly, 49% of the projects studied experienced cost escalations during the implementation period. 60% had to be redone at certain stages of project implementation. Further the study established that the effects of faulty processes included: late deliveries; non-purchase of required items; escalation of procurement budget; delivery of small quantities; delivery of wrong material sizes; non-delivery of ordered items; overpricing among others.Unique Contribution to Theory, Practice and Policy: The study recommends the need to enhance supplier performance through; cross-functional team working of relevant county and national government departments, focused supplier development processes which includes training through continuous exposure to relevant regulatory requirements and improvement in the quality of Project Management Committee membership devoid of political inclinations.

Gender Equity in Leadership and Conferences of the Stroke Society of Australasia

<b><i>Introduction and Aim:</i></b> Internationally, women are underrepresented as leaders in major scientific organizations and conferences. We aimed to determine gender differences in leadership roles and annual scientific conferences of the Stroke Society of Australasia (SSA). <b><i>Methods:</i></b> In a retrospective review of SSA data (2014–2019), committee members were obtained through the SSA Web site, and moderators, speakers, and award recipients were identified from SSA annual scientific conference programs. Gender was determined by name inspection and Web search. Absolute numbers and proportions of women and men were recorded for all roles examined, overall and per year. Associations between representation of women in conferences and percentage of women in speaking roles were tested using multinomial regression. <b><i>Results:</i></b> Presidential leadership of the SSA was held by men in 2014–2016 and 2019 and women in 2017–2018. SSA committee membership was predominantly women (55%), being lowest (47%) in 2014 and 2019 and highest (65%) in 2017. There was a wide gender variation at scientific conferences, with 41% of keynote speakers being women overall, from 20% in 2016 to 75% in 2015. From 2014 to 2019, 55% of all speakers were women, ranging from 32% (in 2016) to 71% (in 2015). A higher percentage of women as speakers or moderators was associated with a program committee with over a third of its members composed of women (<i>p</i> ≤ 0.044). <b><i>Conclusions:</i></b> Representation of women varied from 2014 to 2019 in the SSA organization and its conferences, although men are more often elected president in the organization and women are less often keynote speakers. When more women were included in the program committee, the representation of women as speakers increased.

Peer-making: the interconnections between PhD thesis committee membership and co-publishing

the article relies on the analysis of Social Networks in order to compare the networks at work in the composition of thesis committees between 2003 and 2008 in a French provincial university in three very different disciplines – astrophysics, archaeology and economics – so as to test the hypothesis that connections actually pre-existed to graduation. Were members co-authors of scientific publications or were committees constituted only for the sake of awarding a PhD? Astrophysics and its “equipment” ethos is the one to superimpose most often committee membership and co-publishing. Archaeology falls somewhere in-between, due to the greatest scarcity of committee members. Last of the three, economics actually separates the two types of collaboration by most frequently inviting international researchers. Peer Review https://publons.com/publon/10.1162/qss_a_00143

Audit committee’s attributes, overlapping memberships on the audit committee and corporate risk disclosure: Evidence from Jordan

This paper aims to contribute to the literature by examining whether audit committees' attributes affect risk disclosure practiced by Jordanian listed companies. Selecting a sample of 94 Jordanian companies listed on Amman Stock Exchange, the authors carried out a manual content analysis on annual reports to determine the level of risk disclosure. Random effect model was employed in the analysis. Empirical results show that the audit committee size had a positive effect on the level of risk disclosure. However, there was no evidence that the frequency of the audit committee meetings, expertise or overlapping of the audit committee membership were significantly related to the risk disclosure. The findings are important for standard setters to improve their comprehension about the influence of audit committee in disclosing risk information and reconsider the effective monitoring role played by audit committee.

Fat, Fit, and Fem: Exploring Performative Femininity for Fat Female Librarians

This chapter examines the nature of performative femininity within the context of library service roles, with a particular emphasis on fat women. It addresses the ways fat female bodies are desexualized or are viewed as agender in order to analyze the ways in which this influences fat women in library service roles, and the ways in which fat women are obliged to perform femininity to a greater degree than those with normative bodies. Our sites of analysis look at the expectations around fat women in instructional roles, committee membership, and public service interactions. It has been published in "Deconstructing Service in Libraries: Intersections of Identities and Expectations" (Library Juice Press, 2020).

Järjestöjen vaikuttamistaktiikat internet-aikana: latentti luokka-analyysi

Associations’ tactics of influence in the age of the internet: a latent class analysisThis article examines the use of different influence tactics, including both traditional (e.g., committee membership) and new internet-based tactics (e.g. social media) by interest groups (associations) in Finland. With interest group theory as our theoretical framework, we use data collected in an online survey to explore how different tactics of influence are conjointly utilised. First, a latent class analysis shows that some organizations use almost all tactics more actively than others, including internet-based tactics. Second, we study how a group’s resources and type affect which ‘influencer type’ (active or more or less passive) they belong to. There seems to be no bias related to group type: for example business groups are not more often the most active ones compared to public citizen groups when resources are controlled.