Joint Development of Continuing Engineering Studies Programs: An Example of Industry Education Dialogue Using Ad Hoc Advisory Committees
A política de fomento à pesquisa urbana: subsídios para uma avaliação das avaliações do CNPq
Este trabalho discute aspectos dos processos decisórios do Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), relativos à concessão de bolsas de Produtividade em Pesquisa. Aborda o papel dos Comitês de Assessoramento e dos consultores ad hoc, considerando os critérios para a classificação de pesquisadores em níveis (1 e 2) e categorias (C, B e A), a partir da análise da produção científica nas áreas de Ciências Humanas e Sociais Aplicadas, registrada no Diretório dos Grupos de Pesquisa de 2002. Discute-se o formulário utilizado por consultores ad hoc, apontando-se a necessidade de uma melhor explicitação de critérios avaliativos de projetos de pesquisa, a fim de se obter decisões pautadas por maior rigor e objetividade.Palavras-chave: avaliação; fomento à pesquisa; pesquisa urbana. Abstract: This paper discusses aspects of evaluation processes concerning the concession of research grants by CNPq (Brazil’s funding agency for scientific research and technology). It approaches the role of advisory committees and ad hoc consultants, considering criteria applied to classify researchers in different ranks (1 and 2) and categories (C, B, and A). The discussion of this classificatory system is based on the analysis of researchers’ scientific production presented in the Directory of Research Groups, published in 2002. An analysis of the form used by ad hoc consultants is also presented, pointing out the need for spelling out the criteria applied to assess research proposals, in order to reach more rigorous and objective decisions. Keywords: evaluation; research funding; urban research.
Abstract Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy indicated in the USA for treatment of patients up to 25 years (y) of age with B-cell ALL that is refractory or in second or later relapse. Overall response rate was 82% with 24 months' (mo) follow-up in the registrational ELIANA trial [Grupp et al. Blood 2018]; pooled data from ELIANA and ENSIGN revealed similar outcomes upon stratification by age (<18y and ≥18y) [Rives et al. HemaSphere 2018]. Early real-world data for tisagenlecleucel from the CIBMTR registry reported similar efficacy to ELIANA with no new safety signals [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for patients who received tisagenlecleucel in the real-world setting, stratified by age (<18y and ≥18y). Methods: This noninterventional prospective study used data from the CIBMTR registry and included patients aged ≤25y with R/R ALL. Eligible patients received commercial tisagenlecleucel after August 30, 2017, in the USA or Canada. Age-specific analyses were conducted in patients aged <18y and ≥18y at the time of infusion. Efficacy was assessed in patients with ≥12mo follow-up at each reporting center and included best overall response (BOR) of complete remission (CR), duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). Safety was evaluated in all patients who completed the first (100-day) assessment. Adverse events (AEs) of interest - including cytokine release syndrome (CRS) and neurotoxicity - were monitored throughout the reporting period. CRS and neurotoxicity were graded using the ASTCT criteria. Results: As of October 30, 2020, data from 451 patients were collected, all of whom received tisagenlecleucel. The median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-34). Patients aged ≥18y appeared to have greater disease burden at baseline than those aged <18y, indicated by lower rates of morphologic CR and minimal residual disease (MRD) negativity prior to infusion. Older patients were also more heavily pre-treated before infusion. All other patient characteristics at baseline were comparable between the two groups (Table 1). In the efficacy set (median follow-up 21.5mo; range 11.9-37.2; N=322), BOR of CR was 87.3% (95% CI 83.1-90.7); MRD status was available for 150 patients, of whom 98.7% were MRD negative. Median DOR was 23.9mo (95% CI 12.3-not estimable [NE]), median EFS was 14.0mo (9.8-24.8) and median RFS was 23.9mo (13.0-NE); 12mo EFS and RFS were 54.3% and 62.3%, respectively. For OS, the median was not reached. Efficacy outcomes were generally similar across age groups (Table 1). In the safety set (median follow-up 20.0mo; range 2.6-37.2; N=400), most AEs of interest occurred within 100 days of infusion. Any-grade CRS was observed in 58.0% of patients; Grade ≥3 in 17.8%. Treatment for CRS included tocilizumab (n=113; 28.3% of all patients) and corticosteroids (n=31; 7.8%). Neurotoxicity was observed in 27.3% of patients; Grade ≥3 in 10.0%. Treatment for neurotoxicity included tocilizumab (n=17; 4.3% of all patients) and corticosteroids (n=28; 7.0%). During the reporting period, 82 (20.5%) patients died; the most common cause of death was recurrence/persistence/progression of primary disease. CRS and chimeric antigen receptor (CAR)-T cell-related encephalopathy syndrome were the primary cause of death in 2 patients and 1 patient, respectively. Overall, safety data were similar across age groups, although more patients aged ≥18y experienced any-grade CRS or neurotoxicity and were subsequently treated (Table 1). Conclusions: Updated registry data for pediatric and young adult patients with R/R ALL treated with tisagenlecleucel revealed that patients aged ≥18y had a greater disease burden and were more heavily pre-treated at baseline than patients aged <18y. The overall efficacy and safety profiles of commercial tisagenlecleucel reflected those observed in the clinical trial setting [Grupp et al. Blood 2018; Rives et al. HemaSphere 2018] and were broadly consistent across age groups. Some important differences between the <18y and ≥18y groups were identified, which may point to challenges in timely identification and/or referral of older patients for CAR-T cell therapy. Figure 1 Figure 1. Disclosures Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Margossian: Cue Biopharma, Inc.: Current Employment; Novartis: Other: Ad hoc Advisory Boards. Nikiforow: Kite/Gilead: Other: Ad hoc advisory boards; Novartis: Other: Ad hoc advisory boards; Iovance: Other: Ad hoc advisory boards; GlaxoSmithKline (GSK): Other: Ad hoc advisory boards. Martin: Novartis: Other: Local PI for clinical trial; Bluebird Bio: Other: Local PI for clinical trial. Rouce: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Pfizer: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Redondo: Novartis: Current Employment. Willert: Novartis: Current Employment. Agarwal: Novartis Pharmaceutical Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Pasquini: Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding.
Abstract Introduction: Rearrangements of the MLL (mixed lineage leukemia) gene on chromosome 11q23 are present in 5-10% of either acute myeloid (AML) or acute lymphoblastic leukemia (ALL), and are associated with a poor prognosis. Fusion proteins involving the MLL histone methyltransferase (HMT) result in recruitment of another HMT, DOT1L, to a multi-protein complex leading to aberrant methylation of Histone H3 lysine 79 (H3K79) at MLL target genes and enhanced expression of leukemogenic genes such as HOXA9 and MEIS1. EPZ-5676 is a small molecule inhibitor of DOT1L with sub-nanomolar affinity and >37,000 fold selectivity against additional HMTs. EPZ-5676 treatment of cultured cells reduced histone H3K79 methylation, decreased MLL target gene expression and resulted in selective killing of MLL-rearranged (MLL-r) leukemia cells by inducing apoptosis and differentiation. EPZ-5676 administration led to tumor regression in an MLL-r leukemia xenograft model. We report preliminary results of an ongoing Phase 1 trial of EPZ-5676 in patients with advanced hematologic malignancies, including acute leukemia with MLL-r. Methods: This is a 2-part phase 1 open label dose escalation study investigating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-leukemic activity of EPZ-5676 in adult patients (pts) with relapsed/refractory leukemia (CT.gov: NCT01684150). In the dose-escalation phase, patients with AML, ALL, acute mixed lineage leukemia, myelodysplastic syndrome, myeloproliferative neoplasia (MPN) or chronic myeloid leukemia were eligible. Eligibility in the expansion phase of the study was restricted to pts with MLL-r or partial tandem duplication of MLL (MLL-PTD). EPZ-5676 was administered via continuous intravenous infusion (CIV) for 21 days of a 28 day cycle in the dose escalation phase and CIV for all 28 days of a 28 day cycle in the expansion phase, until disease progression or unacceptable toxicity. Results: Between October 2012 and July 2014, 37 pts have enrolled; 36 are evaluable for safety (received at least 1 dose of EPZ-5676) and 28 pts (19 MLL-r, 4 MLL-PTD) are evaluable for anti-leukemia activity (completed at least one post baseline marrow evaluation). The median age at time of enrollment was 53 years (range: 20 to 81 years); the median number of prior systemic therapies was 2 (range: 1 to 6) and 14 pts had a prior allogeneic stem cell transplant. Of the treated pts, disease characteristics were: 31 pts with AML (21 MLL-r, 5 MLL-PTD), 4 pts with ALL (3 MLL-r) and 1 pt with MPN (MLL-r). Table 1: Number of evaluable pts per cohort Dose (mg/m2/day) 12 24 36 54 80 90 21 day CIV 1 5 4 6 3 - 28 day CIV - - - - - 17 The median time on study was 29 days (range: 5-196 days). Adverse events (AEs) reported in >15% of pts were: anemia, fever/neutropenia, thrombocytopenia, constipation, diarrhea, nausea, chills, fatigue, mucosal inflammation, peripheral edema, hypomagnesemia, dyspnea and sepsis; of which leukocytosis, nausea and hypomagnesemia were assessed by the investigator as drug related. Grade I PR interval prolongation, without associated QTc changes, was observed in 2 pts. There were no deaths attributed to study drug treatment, and there were 2 pts with treatment discontinuation for potentially drug-related AEs. Dose proportional PK was observed with rapid attainment of steady-state plasma concentrations on Day 1 of treatment. Preliminary PD data demonstrated inhibition of H3K79 methylation from baseline in marrow (median: 52%, range 0-81%) and peripheral blood mononuclear cells (median: 43%, range 25-67%) at doses above 36 mg/m2/day. PD effects were observed by day 8. The 21 day CIV pts recovered H3K79 methylation towards baseline by day 28, and the 28 day CIV pts maintained methyl-mark inhibition throughout cycle 1. To date, best responses for pts with MLL-r are morphologic CR (1 pt.), cytogenetic CR (1 pt), and resolution of leukemia cutis (2 pts). In addition, a treatment-related increase in neutrophils (PMN) and/or monocytes was observed in 6 pts with a median day of onset of 15 days (range 8-28 days). The identification of the MLL-r by split signal FISH in mature PMN suggests a differentiation effect on the leukemic clone. Conclusions: EPZ-5676 is well tolerated and exhibits anti-leukemic activity in MLL-rearranged acute leukemia. These data provide rationale for continued clinical investigation of potential utility of EPZ-5676 in patients with rearrangements of the MLL gene. Disclosures Stein: Janssen Pharmaceuticals: Consultancy. Garcia-Manero:Epizyme, Inc: Research Funding. Rizzieri:Novartis, Inc: Consultancy, Speakers Bureau; Ariad, Inc: Speakers Bureau. Savona:Karyopharm: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Altman:Astellas: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Membership on an entity's Board of Directors or advisory committees. Armstrong:Epizyme, Inc: Consultancy. Pollock:Epizyme: Employment, Equity Ownership. Waters:Epizyme, Inc: Employment, Equity Ownership. Legler:Epizyme, Inc: Employment. Thomson:Epizyme, Inc: Employment. Daigle:Epizyme, Inc: Employment, Equity Ownership. McDonald:Epizyme, Inc: Employment. Campbell:Epizyme, Inc: Employment, Equity Ownership. Olhava:Epizyme, Inc: Employment. Hedrick:Epizyme, Inc: Employment; Pharmacyclics, Inc: Equity Ownership. Copeland:New Enterprise Associates: Ad hoc consultant, Ad hoc consultant Other; Mersana: Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Employment, Equity Ownership.
AbstractObjectiveTo examine the workings of the nutrition-related scientific advisory bodies in Europe, paying particular attention to the internal and external contexts within which they operate.DesignDesk research based on two data collection strategies: a questionnaire completed by key informants in the field of micronutrient recommendations and a case study that focused on mandatory folic acid (FA) fortification.SettingQuestionnaire-based data were collected across thirty-five European countries. The FA fortification case study was conducted in the UK, Norway, Denmark, Germany, Spain, Czech Republic and Hungary.ResultsVaried bodies are responsible for setting micronutrient recommendations, each with different statutory and legal models of operation. Transparency is highest where there are standing scientific advisory committees (SAC). Where the standing SAC is created, the range of expertise and the terms of reference for the SAC are determined by the government. Where there is no dedicated SAC, the impetus for the development of micronutrient recommendations and the associated policies comes from interested specialists in the area. This is typically linked with anad hocselection of a problem area to consider, lack of openness and transparency in the decisions and over-reliance on international recommendations.ConclusionsEven when there is consensus about the science behind micronutrient recommendations, there is a range of other influences that will affect decisions about the policy approaches to nutrition-related public health. This indicates the need to document the evidence that is drawn upon in the decisions about nutrition policy related to micronutrient intake.
Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA approved in patients with relapsed or refractory large B-cell lymphomas. While 35-40% of patients may achieve a durable complete response (CR), the toxicity incurred with CAR-T therapy could impact the ability to receive subsequent treatment in those who progress after CAR-T infusion. Our prior data suggested that patients who experienced early progression had inferior overall survival. We now update our results and evaluate the impact of laboratory abnormalities and comorbidities at the time of progression on overall survival. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. Those who exhibited progressive disease (PD) or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined patients who progressed or received additional lymphoma directed therapy after last CAR-T cell infusion as early PD, with all other patients defined as late PD. We collected laboratory data closest to the date of progression. We defined an absolute neutrophil count < 1000, platelet count < 75K, Creatinine > upper limit of normal (ULN), INR > ULN, AST/ALT > 2.5x ULN, total bilirubin > ULN, and LDH > ULN as abnormal. Primary endpoint of this analysis was overall survival (OS) landmarked to date of progression. Secondary endpoints include sub-group analyses based on early PD as well as lab abnormalities at the time of progression. A multi-variate analysis with select baseline and progression variables was also performed. Results: We identified 66 patients who met the above criteria. Median follow up for the entire cohort is 30.4 months (range 0.1-64 months) by reverse KM method. Median time from last planned CAR infusion to progression was 43.5 days (range 11-658). Median OS of the entire cohort was 5.43 months (95% CI 3.75-12.2). 25 (38%) patients experienced early PD, which was associated with inferior OS (median 3.75 vs. 10.4 months, P=0.02). LDH > ULN at the time of progression defined a group with inferior outcomes (median OS 3.16 vs. 17.5 months, P<0.0001). Patients with at least one hematologic abnormality (ANC <1000 and/or platelets < 75K) had similar outcomes to those with higher values (median OS 4.18 vs 9.28 months, P=0.25). However, when we incorporated measurements of organ function, we found that patients with >1 indicator of hematologic and/or organ dysfunction (excluding LDH) at the time of progression had worse outcomes compared to those with one or fewer abnormalities (median OS 1.74 vs. 7.14 months, P=0.001). Multivariate analysis identified pre-CAR IPI score 4-5 (HR 6.33, 95% CI 1.97-20.36), LDH > ULN at progression (7.01, 95% CI 2.89-17.013), and abnormal creatinine at progression (5.32, 95% CI 1.71-16.53), as factors associated with increased risk of death. Conclusions: Patients with PD post CD19-specific CAR T-cell therapy, particularly those with early PD, elevated LDH, or renal failure experience extremely poor outcomes. These data can inform discussion of prognosis for patients who progress after CAR T-cell therapy and may predict which patients may benefit from additional anti-lymphoma therapy. Figure Disclosures Lynch: Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding. Maloney:A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria. Turtle:Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Kite/Gilead: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member. Smith:Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Shadman:TG Therapeutic: Research Funding; Mustang Bio: Research Funding; Atara Biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; ADC Therapeutics: Consultancy; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding. Ujjani:Pharmacyclics: Honoraria; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; Astrazeneca: Consultancy; AbbVie: Honoraria, Research Funding; PCYC: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding.
Abstract Abstract 3702 Introduction: Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to endogenous thrombopoietin, and is approved for the treatment of chronic ITP. ITP is characterized by low platelet counts due to increased platelet destruction and suboptimal platelet production. The response rate to ITP therapies is variable and may be associated with substantial adverse effects. Splenectomy is commonly used as a treatment for ITP because it removes the major site of platelet destruction. A recent consensus report (Provan et al., 2010, 168–86) recommends delaying splenectomy for 6–12 months, in keeping with the new definition for chronic ITP (Rodeghiero et al., Blood 2009, 2386–93); therefore, we evaluated patients who had been diagnosed with ITP ≤1 year who participated in a recent study of romiplostim versus standard of care (SOC). Methods: A randomized, open-label study was conducted in nonsplenectomized adult patients with ITP. The co-primary study endpoints were the incidence of treatment failure and the incidence of splenectomy. Treatment failure was defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule of romiplostim or SOC, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms. The secondary endpoints included platelet counts and safety. Patients who discontinued treatment were considered to have met both primary endpoints. To assess the impact of study discontinuation on the primary endpoints, the actual incidence of treatment failure and splenectomy were also determined (“sensitivity analysis”). An ad hoc analysis of the study endpoints was conducted in those study patients who had been diagnosed with ITP for ≤1 year. Results: Eighty-five of 234 enrolled patients had ITP for ≤1 year; 29 received SOC and 56 received weekly subcutaneous injections of romiplostim. Patient characteristics were similar between treatment groups, as was the distribution of time since ITP diagnosis (romiplostim, 7 – 327 days; SOC 4 – 363 days). The mean (±SD) age was 53 (±20) years and 47% of the patients were male. The mean baseline platelet counts were similar in the romiplostim (26 ± 14 × 109/L) and SOC (23 ± 16 × 109/L) groups. The mean platelet count was higher in the romiplostim arm than the SOC arm at every weekly evaluation until the end of treatment (52 weeks). The incidence of treatment failure was lower in the romiplostim group (9%, 5/56) than in the SOC group (24%, 7/29) [OR, 0.34; 0.10 – 1.14; p= 0.0649]. Similarly, the incidence of splenectomy was significantly lower in the romiplostim group (7%, 4/56) than the SOC group (45%, 13/29) [OR, 0.10; 0.03 – 0.35; p<0.0001]. In addition, romiplostim-treated patients had a significantly longer time to splenectomy than SOC patients (p=0.0001) (Figure). The sensitivity analysis showed that the actual incidence of treatment failure was similar between treatment groups (romiplostim, 5%, 3/56; SOC, 10%, 3/29) [p=0.5589] and the actual incidence of splenectomy was significantly lower in romiplostim-treated patients (4%, 2/56) than in SOC-treated patients (35%, 10/29) [p=.0002]. The percentage of patients experiencing a serious bleeding event was similar (romiplostim, 6%; SOC, 4%). Serious adverse events occurred in 24% (13/55) of romiplostim patients and 46% (13/28) of SOC patients with the most common event being thrombocytopenia. No adverse events led to study withdrawal. Thromboembolic events occurred in one romiplostim-treated patient (pulmonary embolism) and one SOC patient (cerebral microangiopathy). There were no reports of increased reticulin, and no patients tested positive for neutralizing antibodies to romiplostim or TPO. Conclusion: The results from this ad-hoc analysis of this subgroup indicate romiplostim may reduce the incidence of treatment failure and splenectomy in patients who have been diagnosed with ITP for 1 year or less, although the enrollment of patients with platelet counts >20 × 109/L may have contributed to reduced differences in the rates of treatment failure per the study definition. Romiplostim was well-tolerated in this patient population, and findings were similar to those previously reported for the study population overall (Kuter et al., ASH 2009, #679). Disclosures: Boccia: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acendia: Consultancy; Celgene: Equity Ownership, Honoraria, Research Funding, Speakers Bureau; Merck: Equity Ownership; Johnson & Johnson: Equity Ownership; CTI: Research Funding; Cephalon: Research Funding; Millenium: Research Funding. Kuter:Amgen Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Pfizer: Consultancy, Research Funding; Shionogi: Consultancy, Research Funding. Macik:Amgen Inc.: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Grifols: Research Funding; FDA: Consultancy; Center for Biologics Evaluation and Research: Consultancy; Hematology Consultant: Consultancy. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Honoraria. Rodeghiero:Amgen Inc.: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau; Shionogi: Consultancy. Chong:CSL Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wang:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership.
Taskforces, commissions of inquiry, and advisory committees are significant institutional features in the development of government sport policy. This study analyzes New Zealand’s Ministerial Taskforce on Sport, Fitness, and Leisure (2001) and uses empirical data gathered from observations of consultations, interviews with committee members, and available documents. It is argued that procedural, organizational, and political considerations significantly shaped and constrained the Taskforce’s findings and recommendations. Two fundamental contradictions are discussed. The first concerns the expectations for these bodies to develop both innovative and pragmatic recommendations in light of their ad hoc nature, their broad mandates, and short time lines. The second contradiction speaks to the paradoxical nature of taskforces in developing sport policy, noting in particular their dual roles as both advocates for the sport sector and investigators responsible for addressing problems and issues.
Background Iclusig (ponatinib) is a third-generation tyrosine kinase inhibitor (TKI) indicated for adult patients with chronic, accelerated or blast phase CML resistant or intolerant to nilotinib or dasatinib or with Ph+ ALL resistant or intolerant to dasatinib or for patients with the T315I mutation. Long-term efficacy and safety of ponatinib have been demonstrated in clinical trials, but real-world data are still limited. Here, we report the data on ponatinib use in CML and Ph+ ALL patients in routine clinical practice collected over 3 years in Belgium. Methods This ongoing prospective registry (NCT03678454) is conducted in Belgium and includes patients ≥18 years of age eligible for ponatinib treatment per product label. Data on demographics, medical history, disease characteristics, treatment patterns, treatment outcomes and safety were collected for patients enrolled from 1 March 2016 (ponatinib reimbursement in Belgium) onwards. Median follow-up was 15 and 4.5 months for CML and Ph+ ALL patients, respectively. All analyses were descriptive. The study received Ethics Committee approval and patients' consents were collected as per Helsinki Declaration. Results In total, 50 patients (33 CML and 17 Ph+ ALL) were enrolled from 20 hospitals. The median age of CML and Ph+ ALL patients was 58 and 56 years, respectively. 91% of CML and 94% of Ph+ ALL patients had received ≥2, and 54% of CML and 29% of Ph+ ALL patients had received ≥ 3 prior TKIs. Potential risk factors for TKI cardiovascular toxicity were observed: hypertension (17 patients), history of cardiovascular disease (19), smoking (13), hypercholesterolemia (6), hyperlipidemia (5) and diabetes (8). The reasons for starting ponatinib were: intolerance to previous TKIs (20, 40%), refractoriness to previous TKIs (14, 28%), disease progression (8, 16%) or T315I mutation (8, 16%). At entry, 22 patients (44%; 11 CML and 11 Ph+ ALL) had a confirmed BCR-ABL mutation. Of these, 12 (55%; 6 CML and 6 Ph+ ALL) had the T315I mutation. Starting doses of ponatinib in CML patients were: 45 mg (70%), 30 mg (12%) and 15 mg (15%) once daily. One patient with CML started with 15 mg every 2 days. Starting doses in Ph+ ALL patients were: 45 mg (76%), 30 mg (12%) and 15 mg (12%). The median treatment duration was 380 days (range 15-2777) for CML patients and 123 days (range 13-2114) for Ph+ ALL patients, which included recently enrolled patients. Major molecular response (MMR) was achieved as best response in 19 (58%) CML patients and 7 (41%) Ph+ ALL patients; while 2 (6%) of CML and 3 (18%) of Ph+ ALL patients achieved complete cytogenetic response (CCyR) as best response. Of patients who started ponatinib due to intolerance to previous TKIs, 9 CML (64%) and 4 Ph+ ALL (67%) achieved MMR. There were 57 cases (38 in CML and 19 in Ph+ ALL) of dose reduction or interruption, due to AEs (74%), to prevent AEs (25%) and other reason (2%). There were 24 cases (19 in CML and 5 in Ph+ ALL) of dose increase: due to good tolerance of treatment (54%) and absent or low response (46%). At time of analysis, 29 patients (15 CML and 14 Ph+ ALL) had discontinued treatment, for the following reasons: AEs (34%), planned allogeneic transplantation (21%), disease progression (14%), intolerance (3%) and other reasons (28%). Treatment-related adverse events (AEs) were reported in 34 patients (68%); the most common were rash (26%) and dry skin (10%). Six (12%) patients reported ≥1 treatment-related serious AE (SAE): thrombocytopenia (2), palpitations (1), hypertension (1), pneumonia (1), coeliac artery stenosis (1), cholecystitis (1) and hyponatremia (1). One patient, with a history of congenital cardiomyopathy and aortic prosthesis, reported 3 serious cardiovascular events; these were considered as not related to ponatinib by the investigator. Conclusion Results from this real-world Belgian registry support the use of ponatinib in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or have the T315I mutation. Most CML and a large proportion of Ph+ ALL patients obtained deep molecular responses. No new safety signals emerged with ponatinib treatment. The obtained results were in line with those of the PACE clinical trial, with the frequency of cardiovascular events apparently lower, possibly due to selection or improved monitoring of patients, or possible under-reporting vs clinical trial. Longer follow-up will be done to assess the long-term clinical efficiency in this real-life population. Disclosures André: Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding. Bailly:Incyte Biosciences: Other: Local PI of the Study. De Becker:Celgene: Other: ad hoc member of advisory board; Pfizer: Other: ad hoc member of advisory board; Sanofi Pasteur: Other: ad hoc member of advisory board; Incyte: Other: ad hoc member of advisory board. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bekaert:Incyte Biosciences: Employment. Beck:Incyte Biosciences: Employment. Selleslag:INCYTE: Consultancy, Other: Travel Expenses.
Background: IL-15-mediated responses have been shown to have a crucial role in the development, function, and survival of CD8+ T cells, natural killer (NK) cells, and NK T cells. However, exploiting native IL-15 is challenging due to its unfavorable pharmacokinetics and tolerability. NKTR-255 is a polymer-conjugated IL-15 that retains binding affinity to IL-15Ra, maintaining full spectrum of IL-15 biology. NKTR-255 also exhibits improved pharmacokinetics, thereby providing sustained pharmacodynamic responses without the need for daily dosing. Studies have indicated that NK cells from patients with multiple myeloma (MM) appear to be dysfunctional, and successful activity against MM cells requires highly active NK cells ideally activated from immunomodulatory agents or cytokine support. In recent years, several new agents have been introduced in the MM landscape to engage NK-mediated myeloma cell elimination, including the CD38-targeting monoclonal antibody daratumumab, and elotuzumab, further supporting the anti‐MM effect of NK cells in the post-autologous transplant setting. In non-Hodgkin lymphoma (NHL), studies have shown low peripheral blood NK cell counts are associated with poor clinical outcomes in diffuse large B-cell lymphoma patients receiving R-CHOP chemotherapy regimens. Recently published data indicate that NKTR-255 in combination with CAR T cells decreases tumor burden and increases survival compared to CAR T cells alone. NKTR-255 may address the need to boost NK cell quality and numbers in these patients with the purpose of aiding current approved therapies. Methods: In this phase 1, open-label, multi-center, dose escalation and dose expansion study of NKTR-255, patients with relapsed or refractory (r/r) MM or NHL with no available therapies will be eligible. In the dose escalation portion, approximately 46 patients will be enrolled. Successive cohorts of 3 patients each will receive single increasing doses of NKTR-255 until the maximum tolerated dose (MTD) is determined. All patients will receive NKTR-255 once every three weeks. Patients will be observed for a dose-limiting toxicity (DLT) window of three weeks following the first NKTR-255 dose. A two-parameter Bayesian logistic regression model (BLRM) will be used during the escalation part of the study for dose level selection and for determination of MTDs. The selected recommended phase 2 dose (RP2D) of NKTR-255 will be evaluated in two dose expansion cohorts. Cohort A will expand NKTR-255 in patients with r/r MM or NHL as a salvage regimen to further characterize safety and tolerability. Cohort B will combine NKTR-255 with daratumumab in patients with MM with progressive disease who have had at least 3 prior lines of therapy with no other regimens that would confer clinical benefit. Daratumumab will be administered IV at the standard approved regimen. The primary objectives of the study are to evaluate: safety, tolerability, MTD, and RP2D of NKTR-255 as a single agent, as well as safety and tolerability of NKTR-255 in combination with daratumumab in patients with r/r MM. Secondary objectives include measures biomarker and pharmacokinetic analyses. Figure Disclosures Shah: University of California, San Francisco: Employment; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership. Turtle:Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member. Cowan:Cellectar: Consultancy; Juno: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding. Chavez:Kite: 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; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Marcondes:Nektar Therapeutics: Employment, Equity Ownership. Lee:Nektar Therapeutics: Employment. Lin:Nektar Therapeutics: Employment, Equity Ownership. Zalevsky:Nektar Therapeutics: Employment, Equity Ownership. Tagliaferri:Nektar Therapeutics: Employment, Equity Ownership. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding.