A Phase 2 Study to Evaluate the Efficacy and Safety of Selinexor in Patients with Myelofibrosis Refractory or Intolerant to JAK Inhibitors

Background: Selinexor is an oral, small molecule, selective inhibitor of nuclear export (SINE) compound that specifically blocks the karyopherin protein exportin 1 (XPO1, CRM1). In an shRNA library screen, we discovered that the survival of JAK2V167F mutant HEL cells is dependent on XPO1-mediated nuclear-cytoplasmic transport. Selinexor selectively suppressed primary myelofibrosis (MF) cells as compared with normal progenitor cells and induced hematologic responses in an MPN mouse model. Methods: An open label, prospective, investigator-initiated single center study is ongoing in adults with primary or secondary MF with resistance or intolerance to JAK inhibitor (JAKi) therapy with platelets > 30 K/μL and neutrophils > 500/μL. Selinexor was given orally once a week. Spleen volume was assessed by MRI at week 12 and week 24. The study was amended to include additional MRIs every 12 weeks in the year 1 and 24 weeks in the year 2. Primary end point is spleen response, defined as ≥ 35% spleen volume reduction (SVR) by MRI or CT, where applicable) at week 24. Bone marrow was evaluated at baseline and at week 24. The projected sample size of 24 will provide 83% power to reject a response rate of 15% and allow for up to a 25% dropout rate. We provide an interim report after completing 50% enrollment. Results: Between May 2019 and February 2021, 12 patients (pts) were enrolled. JAK2, CALR and MPL mutations were present in 7 (58.3%), 4 (33.3%) and 1 (8.3%) pts respectively. Eight pts (66.6%) had at least one high molecular risk mutation at baseline (Table 1). Median duration of prior JAKi therapy was 22 months (0.5 to 96 months) and 11 out of 12 were refractory to ruxolitinib at study enrollment. Median baseline spleen volume was 1454 cm 3(range 835 to 5792). Selinexor starting dose was 80 mg weekly in the first 6 pts and 60 mg for subsequent pts. At data cutoff, median duration of selinexor therapy was 36 weeks (range 11-114 weeks). One pt was not response evaluable and died due to liver abscess at week 12 (unrelated). One pt discontinued selinexor at week 18 due to grade 3 fatigue and was not evaluable for the primary end point. Of the 11 pts who had week 12 MRI or CT, 6 showed ≥ 10% SVR, 3 showed ≥ 25% SVR and 1 pt had early progression (Figure 1). At week 24, 5/9 (56%) pts had ≥ 25% SVR and 2/9 (22%) had ≥ 35% SVR (Figure 1). In 9 pts who had ≥24 weeks of selinexor, SVR ≥ 25% and ≥ 35% occurred at any point during study treatment in 4 (44%) and 3 (33%) pts, respectively. Two pts were red cell transfusion dependent at baseline; 1 became transfusion independent after 36 weeks of treatment, has not required transfusion for 49 weeks and remains on study treatment to date (114 weeks). Six pts (50%) discontinued selinexor. Reasons for treatment discontinuation are death in 1 pt, progressive disease in 1 pt, alternative treatment in 2 pts, and toxicity in 2 pts. Ten pts required dose reduction due to fatigue (1pt), anemia (1 pt), thrombocytopenia (2 pts), abdominal pain (1pt) and weight loss (5 pts). The most common treatment related adverse event was weight loss (grade 2 in 4 pts and grade 3 in 1 pt). This was manageable with treatment interruption and dose reduction, except in one pt who discontinued selinexor. As yet no changes in reticulin fibrosis MF grade were observed among 9 patients who received at least 24 weeks of treatment. Conclusions: Once weekly, oral selinexor showed single agent activity with sustained spleen responses in pts with JAKi refractory MF. Long-term administration of selinexor was well tolerated over time in MF pts. Correlatives studies including circulating inflammatory cytokine levels and mutant allele burden, as well as clonality studies by X-chromosome inactivation studies in woman, are underway and will be presented. Figure 1 Figure 1. Disclosures Tantravahi: BMS: Research Funding; Novartis: Research Funding; CTI BioPharma: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Patel: Stemline: Research Funding; Genentech: Research Funding; Roche: Research Funding. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. George: Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines: Consultancy. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding.

A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

Systemic mastocytosis (SM) is characterized by mast cell infiltration of ≥ 1 extracutaneous organs and encompasses a spectrum of diagnoses that can range from a non-advanced to advanced disease (Shomali et al, 2018). There are two nonadvanced variants of SM: indolent systemic mastocytosis (ISM), which accounts for approximately 85% and smoldering systemic mastocytosis (SSM), which includes about 5% of the general SM population (Cohen et al, 2014, Jennings et al, 2014). ISM is characterized by 0 or 1 B-findings and SSM by 2 or more B findings and absence of organ damage or an associated hematologic neoplasm (Gotlib et al, 2018). There are currently no approved therapies to treat the underlying disease of ISM or SSM. Although anti-mediator therapies (e.g. anti-H1 and H2 antihistamines, leukotriene receptor antagonists, cromolyn sodium, corticosteroids) are used to control symptoms such as anaphylaxis, GI intolerance, and flushing to improve quality of life, their effectiveness and tolerability are variable. Many patients experience a persistently high symptom burden despite maximized anti-mediator therapies. Because the molecular pathogenesis of SM is driven by KIT D816V mutations in 95% of patients (Garcia-Montero et al, 2006, Jara-Acevedo et al, 2015, Vaes et al, 2017), other agents targeting this mutated kinase have been used to treat the spectrum of SM variants; however, toxicities such as cognitive impairment, GI effects, intracranial hemorrhage, and edema may limit dosing and thus efficacy. In addition to targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Furthermore, bezuclastinib has demonstrated minimal brain penetration and no CNS toxicities have been identified in preclinical studies. Preliminary clinical activity with bezuclastinib has been observed in patients with advanced solid tumors or locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST). A reduction in KIT exon 17 mutational burden was observed in patients treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018). This is a multi-center, Phase 2, double blind, placebo-controlled, 3-part clinical study to evaluate the safety, efficacy, and biomarker correlates (e.g. bone marrow mast cell percentage, serum tryptase level, and KIT D816V mutation burden) of the KIT inhibitor bezuclastinib in patients with ISM and SSM. This study will enroll patients with SSM and moderate-to-severe ISM who have inadequate control of their symptoms despite at least 2 anti-mediator treatments. Part 1 of the study is intended to determine the recommended dose of bezuclastinib in Part 2. Subjects will be randomized to placebo or 1 of 3 doses of bezuclastinib which will be administered in combination with a baseline regimen of best supportive care (BSC). Part 2 will evaluate the efficacy of bezuclastinib at the selected dose as compared with placebo. Efficacy will be measured by the reduction of symptom burden as assessed by the mastocytosis activity score (MAS), a disease specific patient reported outcome tool (Siebenhaar et al, 2018). In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study, including those initially randomized to placebo, may participate in a long-term extension and receive open-label bezuclastinib in combination with BSC. The study will enroll approximately 138 subjects. Data from this study will support further development of bezuclastinib in SM. Disclosures Gotlib: Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Consultancy; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deininger: Novartis: Consultancy, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees. DeAngelo: Incyte: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. Payumo: Cogent Biosciences, Inc: Current Employment. Mensing: Cogent Biosciences, Inc.: Current Employment. Jolin: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. George: Bristol Meyers Squibb: Consultancy; Blueprint Medicines: Consultancy; Celgene: Consultancy; Incyte Corporation: Consultancy. OffLabel Disclosure: study of investigational agent

Exploiting LY3009120 and Asciminib Combination to Target TKI-Resistant CML

The oncogenic BCR-ABL1 tyrosine kinase is the driver of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Tyrosine kinase inhibitors (TKIs) targeting ABL kinase are generally effective, but subsets of patients treated with single-agent TKIs develop resistance due to mutations in BCR-ABL1 that impair TKI binding. We have previously reported that BCR-ABL1 compound mutants (exhibiting two mutations within the same BCR-ABL molecule) that include the T315I gatekeeper mutation confer a high degree of resistance to all clinical ABL TKIs used as single agents, including ponatinib and the allosteric inhibitor asciminib. However, combining asciminib with ponatinib provides an effective strategy for overcoming compound mutation-based resistance (Eide et al. Cancer Cell 2019). As the clinical utility of ponatinib is limited by cardiovascular toxicity, including arterial occlusive events (AOEs), we decided to search for alternative molecules for use in combination with asciminib. To identify functional ponatinib analogs, we performed Quantum Similarity Modeling (QSM) on the reported crystal structure of T315I mutant ABL1 kinase in complex with nilotinib and asciminib (5MO4) (Wylie et al. Nature 2017) to search for other molecules. Compared to conventional computational modeling, QSM identifies novel classes of structurally distinct compounds that are comparable on a quantum level by precisely defining their interaction with the target. Affinity inferred by close complementarity with the shared ligand-protein surface in the region of the surveyed binding site is mapped, using multiple weak local associations. Our in silico QSM platform combines quantum methods with machine learning to investigate extensive chemical spaces. We screened several million compounds against BCR-ABL1 and identified 51 potential candidates predicted effectively to block T315I mutant BCR-ABL1 when combined with asciminib. To prioritize potent and non-toxic drug combinations for further development against compound mutants, we initially profiled all 51 compounds for their efficacy against Ba/F3 BCR-ABL T315I cells, alone and in combination with asciminib (1 nM). Of 51 compounds, LY3009120, a pan-RAF inhibitor that is currently in phase I clinical development for advanced solid malignancies (Sullivan et al. Mol Cancer Ther 2020), showed strong activity against BCR-ABL T315I when combined with asciminib. These data provided proof of principle for the QSM approach. We next tested the efficacy of all 51 candidates ± asciminib against Ba/F3 cells harboring T315I-inclusive BCR-ABL1 compound mutants, including Y253H/T315I, E255V/T315I, H396R/T315I, G250E/T315I, and T315L as the most resistant mutants. Neither single agent showed any effect. However, LY3009120 strongly inhibited BCR-ABL1 compound mutants when combined with asciminib. No toxicity was observed against Ba/F3 parental cells, confirming that the effects of the combinations are mediated by inhibition of BCR-ABL1. Synergy quantification of the dose-response matrix for the LY3009120/asciminib combination using the Zero Interaction Potency model demonstrated highly synergistic interactions (Synergy score > 10) between the two inhibitors. To directly assess the binding affinity of LY3009120 to the ABL1 kinase domain, we used the cell-based NanoBRET intracellular ABL1 kinase assay on HEK-293 cells expressing luciferase-tagged ABL1. The NanoBRET assay uses energy transfer to quantify the affinity of test compounds by competitive displacement of a cell-permeable fluorescent tracer that is reversibly bound to an ABL1-luciferase fusion protein. We found that LY3009120 competes off the fluorescent tracer at a low micromolar range (EC 50 = 0.75 μM), confirming direct binding of LY3009120 to the kinase domain of ABL1. We hypothesize that the binding of LY3009120 to the ABL1 kinase domain induces a conformational change that re-establishes asciminib binding to the myristoyl binding pocket, allowing for synergy. Studies to quantify the binding affinity of LY3009120 and asciminib to BCR-ABL1 mutants are underway, and data will be presented. In summary, our findings validate QSM as a novel in silico approach to identify TKI combinations. Combining LY3009120 with asciminib may be an effective, low-risk strategy to target BCR-ABL1 compound mutants in patients with clinical TKI resistance. Disclosures Deininger: SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Novartis: Consultancy, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding.

THE INFLUENCE OF HIGHER EDUCATION ON THE ACQUISITION OF STUDENTS’ KNOWLEDGE, SKILLS AND COMPETENCES REQUIRED IN THE LABOUR MARKET

Institutions of higher education, among other duties and responsibilities, prepare students to enter the labour market. The aim of this paper is to determine the extent to which higher education prepares students for the foreordained transition from the educational system to the labour market. The research was conducted in the form of a survey by which the students of the final years of the professional undergraduate study Management and the graduate professional study Management at the College of Slavonski Brod carried out a self-assessment of their knowledge, skills and competencies. To present and elaborate prerequisites of education as preparation for the labour market, characteristics of the labour markets and employment policy measures as well as knowledge, skills and competencies that are required on today's labour market and for the purpose of conducting this research, the following scientific methods were used: analysis and synthesis, historical method, comparative method, induction and deduction and statistical method. Results of this research indicate; if the students in the final years, of both, the undergraduate study and the graduate study, have the necessary knowledge, skills and competences that employers require of their employees, then students will consider themselves more prepared to find a job. In that regard, it is expected that each higher education institution provides students with the necessary knowledge, skills and competences i.e. those that enable students to cope well with the challenges of the labour market.

Debt to Assets Ratio and Management Asset on Financial Performance: an Evidence of Chemical Companies in Indonesia Stock Exchange

This study aims to analyze the effect of Debt to Asset Ratio and Management Asset on Financial Performance in chemical companies listed on the Indonesia Stock Exchange. The population used in this study are chemical companies listed on the Indonesia Stock Exchange. The sample used in this study was 9 companies in 2015-2019, so that 36 research samples were obtained. In this study, Management Asset is measured using the Inventory Turnover proxy and Financial Performance using the Return on Assets proxy. Based on research, simultaneously, Debt to Asset Ratio and Management Asset have a significant effect on Financial Performance. While partially the Debt to Asset Ratio has an influence on the Return on Asset and Management Asset has no effect on the Return on Asset. Debt to Assets and Inventory Turnover ratios contributed 53.8% to Return on Asset.

Assessment and Management of Eyelid Injury

Background and aim: Among all sites of injury, eyelid laceration seems to be neglected in terms of sufficient epidemiological investigations. With a thorough understanding of the causes of eye lid lacerations, it is possible to develop a better preventive strategy and hence improve the public health policy in this respect. Hence the aim of the study was to understand the type of eyelid injury and study management of the injuries. Materials and methods: A total of 100 cases that were reported to the hospital department opd with the chief complain of blunt as well as penetrating eye lid injuries were included in the study. Evaluation by a physician was done for all cases to note the presence of any systemic diseases and for opinion regarding fitness for surgery. In cases where General Anaesthesia (GA) was used, Anaesthetist examined the patient and opined regarding status of the patient towards GA. Results: The results of the present study showed that 3rd and 4th decade were more prone to the eyelid injuries. Majority of the 58 cases showed involvement of left eye whereas the involvement of right eye was seen in 42 cases. In the present study, Minimonoka stent was used for 8 cases of canalicular lacerations and 8 cases of canalicular tear that were not affordable were repaired with 24G Venflon tube. Conclusion: As the injuries occur more commonly due to road traffic accidents showing 54 cases in our study, preventive measures are to be taken while riding such as controlling speed. Domestic injuries are more common in females. This study showed that Minimonoka stent is an effective and easy tool in reconstructing canalicular tear, with successful anatomical and functional integrity.

Anesthesia Management in Achondroplasia: A Case Report

Achondroplasia is the result of a mutation in the gene encoding the type 3 receptor for a fibroblast growth factor. This abnormality results in malformation endochondral ossification. Achondroplasia is characterized by disproportionately short stature, lumbar lordosis, large head, midface hypoplasia, short hands, and normal cognitive development. Our report is about a 28-year-old patient with achondroplasia who underwent surgery for correction of kyphosis due to spinal canal stenosis. In this present case we study management anesthesia.

Adoption Level of Good Aquaculture Practices in Brackish Water Pond Aquaculture, Pinrang Regency, South Sulawesi Province

Pinrang Regency is a center of brackish water pond aquaculture production in South Sulawesi Province in which some of brackish water pond farmers in this regency have adopted Good Aquaculture Practices (GAqP). A study was conducted to determine GAqP adoption level, to identify GAqP aspects required to be improved, and to determine the category of GAqP adoption level as the first step to maximize the GAqP adoption level in the brackish water ponds. Primary data were obtained from 76 respondents consisted of pond farmers who already have adopted and or obtained GAqP certificates. On the basis of the adoption level, the adoption level classification is carried out into three categories, namely low adopters, medium adopters, and high adopters. The results showed that the highest GAqP adoption levels in brackish water ponds were in food security (89.41%) and technical aspects (78.57%). The lowest GAqP adoption levels were in management (8.71%) and environmental aspects (0%). It was also reported that the GAqP adoption level in brackish water ponds varied from 40.58 to 67.01% with an average of 42.86% and was categorized as moderate adopters. Based on this study, management and environmental aspects were found to be the aspects that need serious attention to increase the GAqP adoption level in the brackish water ponds.