Academic literature on the topic 'Grant-free scheduler'

5130 Background: PFS has been proposed as an endpoint in prostate cancer because tumor regression cannot be assessed easily and the significance of post-therapy changes in PSA is uncertain. There is significant variability in the frequency by which outcomes are assessed across clinical trials. We sought to create a model that would define the degree of error in estimating PFS from this variability. Methods: A simulation experiment was performed. An exponential distribution was used to generate 100 progression times for 3 hypothetical risk cohorts: rapid (median PFS of 18 wks), intermediate (36 wks) and slow progressors (72 wks). We examined how reported PFS would change depending on 3 assessment schedules: every (q) 6, 8 and 12 wks for 48 wks each, then q6 months for 2 years. The logrank statistic was used to compare PFS between schedules. If different schedules have no impact the expected type 1 error rate should be 5% (where a difference in PFS time is detected when none existed). Each simulation was repeated 1000 times. Results: Nine pairwise comparisons were performed and Kaplan-Meier PFS estimates created for the 3 assessment schedules and 3 risk cohorts (see table 1 ). In the highest risk cohort, PFS of 18 wks, 38% of the time the logrank test showed a falsely prolonged PFS for pts assessed on the q12 vs 6 wks schedule. This type 1 error rate (by simulation) was reduced to 20% and 11%, when the schedules were q8 vs 12 wks and q6 vs 8 wks, respectively, but remained above the 5% expected rate for type 1 error. For lower risk pts, PFS of 72 wks, the disparity in PFS times was diminished. Conclusions: Progression free survival is significantly skewed by the schedule of assessing treatment effects in clinical trials. This argues for uniformity in the timing of outcome assessments across trials and between arms in randomized trials. Grant support: 5T32CA09207 [Table: see text] No significant financial relationships to disclose.

Education is a very important determinant of overall development of a community or a society. It is the responsibility of a state in democratic country like India to provide equal opportunity of qualitative educational development to all sections of the society. Distance education is mainly focused on democratization of higher education by providing a platform to disadvantageous section of people due to some unavoidable circumstances. It facilitated them; get the hands on training through distance mode without hampering the daily social responsibilities and activities of learners. IGNOU BSW programme is one of the important professional based programme for learners dealing with professional training/degree in Social Work. India’s Northeast region is popularly celebrated for its cultural diversity with sizable number of Schedule Tribe (ST) community as inhabitant of this region. Social Work Education in the Northeast region of India began only in the year 1992. The present study is carried out on 620 learners of BSW programme enrolled at IGNOU RC, Guwahati in last ten years from 2010 to 2019 with an intention to assess the impact of IGNOU fee exemption scheme in admission of Scheduled Caste (SC) and Scheduled Tribe (ST) learners in undergraduate programmes. This will enable us to know and assess the participation/ involvement of SC/ST learners in free admission scheme of IGNOU under SCSP/TSP Grant in Assam by examining their percent shares in annual admission. Apart from that we have also examined the overall general trends of admission on the basis of Area (Urban, Rural & Tribal), Gender, the age profile, and marital status of learners enrolled in this programme. This study is undertaken to determine and access the fulfilment of University’s motto “reaching the unreached” in weaker section and scheduled communities of our society.

Abstract Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, with 5-year survival <20%. CD22 is expressed on lymphoblasts in >90% of pts with B-ALL and is an established therapeutic target. ADCT-602 is an antibody drug conjugate composed of a humanized monoclonal antibody directed against CD22 and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, ADCT-602 demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present here interim data from an ongoing Phase 1/2 trial evaluating ADCT-602 in pts with R/R B-ALL (NCT03698552). Methods: This is an investigator-initiated Phase 1/2 trial of ADCT-602 monotherapy in pts with R/R B-ALL. The primary objective of the Phase 1 part is to assess the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ADCT-602. The primary objective of Phase 2 is to evaluate efficacy (CR/CRi rate). Secondary objectives include duration of response (DOR), progression-free survival (PFS) and overall survival (OS), and characterize the pharmacokinetic (PK) profile of ADCT-602. Eligible pts must be ≥18 years of age with R/R B-ALL with bone marrow blasts ≥5%. CD22 must be expressed in ≥20% blasts. Pts must have adequate organ function (creatinine ≤1.5 mg/dL; ALT and AST ≤2 times upper limit of normal (ULN), ≤5 times ULN if there is liver or bone involvement; total bilirubin ≤1.5 times ULN; LVEF ≥45%). In part 1, pts were assigned to treatment according to a 3+3 dose-escalation design. ADCT-602 was initially given IV once every 3 weeks; recently, based on the PK data, the administration schedule was amended to weekly infusions. Results: From November 2018 to June 2021, 14 pts (8 male, 6 female) with B-ALL have been treated with ADCT-602. The median age was 39.5 years (range, 22-82) and pts had received a median of 5 (range, 2-7) prior therapies [inotuzumab ozogamicin 10/14 (71%); blinatumomab 13/14 (93%); venetoclax 10/14 (71%); CD19 CAR 5/14 (36%)]. Seven (7/14, 50%) pts had a prior allogeneic stem cell transplant (allo-SCT), including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70.5% (range, 16-95). The median CD22 expression on blasts was 90.5% (range, 33.6-99.9). A total of 11 pts were treated in the Q3week schedule [30µg/kg, n=3; 60µg/kg, n=4; 90µg/kg, n=4]. As the PK data (shown below) indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing and 3 pts have been treated at 30µg/kg weekly dose level. No pt had a DLT. Two pts (one each at 60µg/kg and 90µg/kg every 3 weeks schedule) did not complete the DLT window due to rapid disease progression and were taken off treatment prior to day 28. One pt (in the weekly schedule) had grade 4 thrombocytopenia possibly related to ADCT-602. No pt had veno-occlusive disease. Two pts achieved MRD-negative remission. One pt was 35-year-old with R/R B-ALL (complex karyotype, NRAS mutation) with several prior lines of therapy (HCVAD, pegasparaginase-based therapy, allo-SCT, inotuzumab, POMP). Baseline bone marrow blasts were 87% with 99.9% CD22 expression. Pt received ADCT-602 at 30µg/kg Q3week schedule and achieved MRD negative CRp after Cycle 1 which improved to MRD negative CR after Cycle 2. He received a total of 6 cycles of ADCT-602 before transitioning to second allo-SCT. Another pt was 22-year-old with R/R B-ALL (complex karyotype) with multiple prior therapies (including 2 prior allo-SCT, CD19 CAR-T, inotuzumab, blinatumomab, pegasparaginase, venetoclax) received ADCT-602 at 30µg/kg weekly schedule. Baseline bone marrow blasts were 24% with 97% CD22 expression. Pt achieved MRD negative CRp after Cycle 1 and is currently receiving Cycle 2. PK data, available for 9 pts treated at every 3-week schedule [30 mcg/kg, n=3; 60 mcg/kg, n=4; 90 mcg/kg, n=2] showed rapid clearance of antibody with mean apparent half-life of <1 day during Cycle 1. This supported transitioning ADCT-602 administration to the weekly dosing. Conclusions: In this Phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with no DLTs noted. Two pts achieved MRD-negative remission. Dose escalation in the weekly schedule continues and 2 additional dose levels (40µg/kg weekly and 50µg/kg weekly) are planned. Disclosures Jain: Aprea Therapeutics: Research Funding; Janssen: Honoraria; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; Beigene: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Sanofi: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Calithera: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Cellectis: Other: grant support; Stemline Therapeutics: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; KisoJi: Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Dan's House of Hope: 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; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Thompson: Amgen: Other: Institution: Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria. Short: Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kadia: Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; AstraZeneca: Other; Cure: Speakers Bureau; BMS: Other: Grant/research support; Jazz: Consultancy; Liberum: Consultancy; Sanofi-Aventis: Consultancy; Pulmotech: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Borthakur: GSK: Consultancy; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Daver: Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Genentech: 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. DiNardo: Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Ravandi: Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding. Kantarjian: Astellas Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. OffLabel Disclosure: ADCT-602 is not approved for B-ALL

Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are a common indication for allogeneic hematopoietic stem cell transplant (HCT) in first complete remission (CR1). Despite HCT, relapses are common and cure rates are limited thereafter. The use of FLT3 inhibitors as post-HSCT maintenance therapy has not been prospectively evaluated in the phase 3 setting. Gilteritinib is a selective, potent FLT3 inhibitor with robust activity and favorable tolerability in relapsed/refractory AML. This trial will compare the safety and efficacy of 2-year maintenance therapy with gilteritinib versus placebo in patients with FLT3-ITD+ AML in CR1 after allogeneic HSCT. The broad goal of this study is to determine if there is a benefit to FLT3 inhibition as maintenance therapy post-HCT and to identify which patients, if any, benefit. We will use a novel NGS-based assay for FLT3-ITD mutations to detect minimal residual disease (MRD) in order to stratify patients pre-HSCT and correlate with relapse post-HCT. Study Design and Methods: This Phase 3, randomized, double-blind, placebo-controlled multicenter trial (NCT02997202; Blood and Marrow Transplant Clinical Trials Network Protocol 1506), is being conducted at 149 sites worldwide. The target enrollment is 532 adult subjects (aged ≥18 years) with FLT3-ITD+ AML in CR1 who are ≥30 days and ≤90 days from scheduled allogeneic HSCT. Of these 532 subjects, 346 subjects who have achieved successful engraftment without uncontrolled graft-versus-host disease (GVHD) or other serious toxicity will be randomized (1:1; stratified by conditioning regimen intensity, time from HSCT [Day 0] to randomization [30-60 days vs 61-90 days], and presence of minimal residual disease [MRD] in the pre-transplant bone marrow sample) to receive oral gilteritinib (120 mg) or matching placebo as maintenance therapy for 2 years. The primary endpoint is relapse-free survival (RFS) in the two treatment arms; RFS will be assessed from the time of randomization to the time of death or morphologic leukemia relapse (as defined by Revised IWG criteria). MRD status will continue to be monitored over the duration of the maintenance therapy, although investigators will be blinded to the MRD assay results. Overall survival is a key secondary endpoint. Other endpoints include safety/tolerability, non-relapse mortality, event-free survival, incidences of acute/chronic GVHD, and MRD. As of July 31, 2019, 341 patients have been registered and 236 have been randomized. To achieve a target number of 346 subjects for randomization (n=173 per treatment arm), we estimated that enrollment of 532 subjects would be required given an expected dropout rate of 35% between the time of registration to the time of randomization. The RFS rate in the placebo arm (control) is assumed to be 67% at 1 year, 59% at 2 years, and 55% at 3 years (according to the Center for International Blood & Marrow Transplant Research data for FLT3-ITD+ patients transplanted in CR1 who were alive and were progression free at 60 days). A total of 122 events will provide 85% power to detect a hazard ratio (HR) of 0.57 (corresponding to a 15% difference in 2-year RFS) with two-sided significance level of 0.05. With a 2-year accrual period and a 5% annual dropout rate, enrollment of 346 subjects will ensure a high probability of obtaining 122 events. The primary efficacy analysis will be performed using the intention-to-treat (ITT) population, which is defined as all subjects who are randomized. RFS will be compared across the treatment groups using the stratified Log-rank test. A stratified Cox model with treatment as covariate will be used to determine HR and confidence intervals at 1, 2, and 3 years. Kaplan-Meier estimates of RFS will be reported at 1, 2, and 3 years. No interim efficacy or futility analyses are planned. Figure Disclosures Levis: Daiichi Sankyo Inc: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Merck: Research Funding; Janssen: Consultancy. Rosales:Astellas: Employment. Delgado:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Horowitz:Actinium: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant. Chen:Incyte: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Takeda: Consultancy.

Abstract Introduction: In recent decades, a considerable number of tumor antigens have been characterized, including the leukemia-associated antigen, Wilm's tumor 1 (WT1). WT1 is found to be expressed at low levels in various normal tissues such as gonads, kidney and the hematopoietic system. However, it is highly overexpressed in various hematological malignancies and solid tumors, including in the majority of acute myeloid leukemia (AML) cases. OCV-501 is a human leukocyte antigen (HLA) class II-restricted helper peptide derived from the WT1 protein. This Phase II trial was conducted to evaluate the efficacy and safety of OCV-501 in elderly patients with AML (ClinicalTrials.gov identifier: NCT01961882). Methods: This multicenter, randomized, double-blind, placebo-controlled trial was conducted in Japan, the Republic of Korea and Taiwan between October, 2013 to November, 2017. The key eligibility criteria for this trial were patients with AML, aged 60 years or older, who achieved first complete remission within one or two courses of standard induction therapy, completed more than one course of standard consolidation therapy, and not scheduled for hematopoietic stem cell transplantation. Patients were assigned to receive either OCV-501 monotherapy or placebo. Subcutaneous administration of OCV-501 3mg or placebo was given once weekly up to the eighth administration, and once biweekly from the ninth administration onwards up to a duration of 2 years, followed by post-treatment observation period. The primary endpoint was disease-free survival (DFS) that was defined as the time from randomization to AML relapse or death from any cause, whichever came first, within the observation period. Secondary endpoints were overall survival (OS), quality of life (QOL; The European Organization for Research and Treatment of cancer [EORTC] QLQ-C30), and performance status (Eastern Cooperative Oncology Group performance status [ECOG PS]). Safety, including any occurrence of adverse events (AEs) was evaluated. Results: A total of 133 patients who had achieved first remission after prior induction and consolidation therapies were randomized to receive either OCV-501 (OCV-501 arm, N=68) or placebo (placebo arm, N=65). The median age of the patients was 67 years (range, 60 - 85) and most of them had good performance status (ECOG PS score 0 - 1). The WT1 mRNA level at Day 1 was <50 copies/μg RNA in 37 patients in the OCV-501 arm and 28 patients in the placebo arm. In the evaluation of efficacy, there was no significant difference in DFS between both arms, and the median DFS was 12.1 months and 8.4 months in the OCV-501 arm and placebo arm, respectively. The median OS was 38.5 months and 31 months in the OCV-501 arm and placebo arm, respectively. The results of patient QOL and PS were similar between both arms. Overall, there were no significant safety findings throughout the trial. A majority of the patients in both arms had at least 1 treatment-emergent AE (TEAE); however, most of the TEAEs were mild in severity (Grade 1 or 2). The most frequently reported TEAE was site injection induration. Conclusion: There was no significant difference in DFS between OCV-501- and placebo-treated patients. OCV-501 was found to be generally safe and well-tolerated in elderly AML patients. Disclosures Yamaguchi: Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; Celgene KK: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria. Kiguchi:Teijin Co., Ltd.: Other: Grant; Sanofi K.K., Ltd.: Other: Grant; Celltrion, Inc.: Other: Grant; Taiho Pharmaceutical Co., Ltd.: Other: Grant; SymBio Pharmaceuticals, Ltd.: Other: Grant; Takeda Pharmaceutical Co., Ltd.: Other: Personal fees; Ono Pharmaceutical Co., Ltd.: Other: Personal fees; Astellas Pharmaceutical Co., Ltd.: Other: Grant; Celgene Co., Ltd.: Other: Grant and personal fees; Janssen Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Novartis Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Nippon Shinyaku Co., Ltd.: Other: Grant and personal fees; Mochida Pharmaceutical Co., Ltd.: Other: Personal fees; Eisai Co., Ltd.: Other: Personal fees; MSD Co., Ltd.: Other: Grant and personal fees; Daiichi Sankyo Pharmaceutical Co., Ltd.: Other: Grant; Chugai Pharmaceutical Co., Ltd: Other: Grant; Bristol Myers Squibb Co., Ltd.: Other: Grant and personal fees; Pfizer Co., Ltd.: Other: Personal fees; Otsuka Pharmaceutical Co., Ltd.: Other: grant and personal fees; Kyowa Hakko Kirin Co., Ltd.: Other: Grant and personal fees. Miyawaki:Novartis Pharma KK: Consultancy; Otsuka Pharmaceutical Co., Ltd.: Consultancy; Astellas Pharma Inc.: Consultancy. Heike:Sumitomo Dainippon Pharma Co., Ltd.: Other: Advisor; Otsuka Pharmaceutical Co., Ltd.: Other: Advisor. Mitsuki:Otsuka Pharmaceutical Co., Ltd.: Employment. Yoshida:Otsuka Pharmaceutical Co., Ltd.: Employment. Liew:Otsuka Pharmaceutical Co., Ltd.: Employment. Naoe:Astellas Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Toyama Chemical Co., Ltd.: Research Funding.

15165 Background: Paclitaxel (T), cisplatin (P), and 5-fluorouracil (5-FU) are active chemotherapy drugs for esophageal cancer. The 3-drug combination using a conventional 3-weekly schedule was active in patients with advanced esophageal cancer with response rate of 46% (Ilson DH et al: J Clin Oncol 1998;16:1826). The toxicity was substantial, with 57% grade 3/4 hematologic toxicities and 18% grade 3/4 peripheral neuropathy. We reported a multifractionated schedule using twice-weekly TP and weekly 5-FU (Lin CC et al: Anticancer Drugs 2007;18: in press). The multifractionated schedule, while induced comparable antitumor activity, had similar hematologic toxicities, less neuropathy, but more diarrhea than conventional 3-weekly schedule. The optimal way of combining T, P, and 5-FU remains to be defined. Methods: Patients with metastatic or recurrent esophageal cancer treated with weekly T, P, high-dose 5-FU plus leucovorin (weekly TP- HDFL) were retrospectively analyzed. The regimen consisted of T 70–80 mg/m2 IV 1h D1, P 35 mg/m2 IV 3h D2, 5-FU 2000 mg/m2 plus leucovorin 300 mg/m2 IV 24h D2, for 2 or 3 weeks followed by 1 week off. Results: Between Dec 2004 and Sep 2006, a total of 15 patients (male 14, squamous cell carcinoma 12) with a median age of 54 (range 37–76) were included. Eleven patients had de novo metastatic disease and 4 had recurrent disease. The disease extent included local esophageal tumor, lymph nodes, lung, liver, and bone in 13, 13, 5, 4, and 5 patients, respectively. The patients received an average of 3 cycles (range 1–5). Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and infection occurred in 4, 3, 1, and 5 patients, respectively. No grade 3/4 vomiting, mucositis, diarrhea, and peripheral neuropathy occurred. The overall response rate was 33% (95% CI 12–87) (PR 5, SD 6, PD 4). With a median follow-up of 5 months, the median progression-free and overall survival were 3 (range 2–7) and 12.5 months (range 3+-12.5), respectively. Conclusions: Weekly TP-HDFL has a comparable activity and a better toxicity profile in patients with advanced esophageal cancer compared to previously reported 3-weekly or multifractionated schedule. (The study was supported by the grant of DOH95-TD-B-111- 001) No significant financial relationships to disclose.

Abstract Introduction Sleep has been shown to affect cognitive function in laboratory studies; however, its association to the academic performance of adolescents has largely been demonstrated using self-reported measures. Studies with objective measures of both sleep and academic performance are limited. The aim of the present study was to determine whether the free-living sleep quantity, quality, and timing of 15-year-old adolescents measured with wrist actiography are associated with their scores on national standardised examinations as an objective measure of academic achievement. Methods We measured sleep with wrist actiography for 1 week in 253 (150 girls) Icelandic adolescents with a mean (SD) age of 15.9 (0.3) years. Multiple linear regression was used to assess associations between sleep parameters and combined standardised examination scores in mathematics, English, and Icelandic obtained from the Icelandic Directorate of Education. Results We found that students went to bed at 00:49 hours (± 51.8 min) and slept for a mean (SD) of 6.6 (0.7) hr/night, with a median (interquartile range) night-to-night variation in sleep duration of 1.2 (0.7) hr and an efficiency of 88.1 (5.3)%. Combined analyses adjusted for sex, demonstrated that both bedtime and night-tonight variability in total sleep time were negatively associated with the average score across all topics. Sex-specific associations did not indicate clear differences between boys and girls. Conclusion These findings suggest that, in addition to appropriate sleep duration, public health guidance should also highlight the importance of early and consistent sleep schedules to academic achievement for both boys and girls. Support (If Any) National Institute of Diabetes and Digestive and Kidney Diseases intramural research program, Grant/Award Number: Z01 DK071013 and Z01 DK071014; Icelandic Centre for Research, Grant/ Award Number: 152509-051

Abstract Background: Leukemic relapse and graft-versus-host disease (GvHD) remain major obstacles after an allogeneic stem cell transplantation (HSCT). Panobinostat is a potent inhibitor of class I, II and IV deacetylases and has shown antileukemic as well as immunomodulatory activity. The hypothesis of our phase I/II PANOBEST trial was that panobinostat can effectively prevent relapse in patients (pts) with high-risk (HR) myeloid diseases while simultaneously reducing GvHD. We aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of panobinostat in adult pts with HR acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) in complete hematologic remission (CR) after a reduced-intensity HSCT. Secondary objectives were evaluation of safety and tolerability of panobinostat, and overall (OS) and disease-free survival (DFS) at 1 and 2 years after HSCT. Methods: In two sequential schedules, panobinostat was administered orally thrice weekly, (TIW), either every week (A) or every other week (B). In schedule A, panobinostat was started at a dose of 10 mg TIW and escalated to 30 mg TIW using a 3+3 design; in schedule B, panobinostat was given at doses of 20-40 mg TIW. Panobinostat was initiated between day +60 and +150 after HSCT and given for up to 1 year. Eligibility criteria included: ANC ≥ 1,000/μL, platelets ≥ 75,000/μL, adequate organ function and no severe GvHD. DLT was defined as prolonged G4 hematologic toxicity or any non-hematologic toxicity ≥ G3 unrelated to disease progression or intercurrent illness within 28 days of the first panobinostat dose. Results: 42 pts (37 AML, 5 MDS) were enrolled, with a median age of 52 years (range, 21-71). Cytogenetics were classified as low (n=6), intermediate-1/2 (n=20) or adverse risk (n=16) according to ELN criteria. Panobinostat was started a median of 98 days (range, 60-147) after HSCT from a matched related (n=9), matched unrelated (n=24), mismatched unrelated (n=6) or haploidentical donor (n=3). The majority of patients (n=28, 67%) were transplanted with active disease (bone marrow blasts 0-80%, median 21%, 1 pt. with extramedullary AML), 9 in CR1 (21%) and 5 in CR2 (12%). Patient and transplant characteristics were equally distributed between schedules A and B. Of 42 pts, 22 (54%) have completed one year of panobinostat, 1 remains on treatment and 19 (46%) discontinued prematurely after a median of 70 days (range, 12-342) due to adverse events (AEs) (n=10), relapse (n=6), patient decision (n=2) or prohibited comedication (n=1). To date, 24 out of 42 patients experienced panobinostat-related grade 3/4 AEs (schedule A: n=14, 67%; schedule B: n=10, 48%). The most common AEs were hematologic toxicity (G3: 14 pts, 33%; G4: 2 pts, 5%), constitutional (G3: 7 pts, 17%) and gastrointestinal symptoms (G3: 5 pts, 12%). Neurological AE and pain (G3, 2 pts each, 5%) as well as metabolic/laboratory alterations (G3: 3 pts., 7%) and renal toxicity (G3, 1 pt, 5%) were also reported. AEs were fully and rapidly reversible after interrupting panobinostat (n=24); 14 patients needed dose adjustment and no study-related deaths occurred. The RP2D was 20 mg TIW in arm A and 30 mg TIW every other week in arm B based on 5 DLTs: fatigue G3 at 20 mg, colitis and nausea/emesis G3 each at 30 mg (arm A), diarrhea and headache G3 at 40 mg each (arm B). Prophylactic or preemptive donor lymphocyte infusions (median 2, range, 1-6) were administered to 10 pts (42%, median 1.5x106 CD3+ cells/kg) in arm A and 8 pts (33%, median 0.5x106 CD3+ cells/kg) in arm B. Cumulative incidence (CI) of moderate (n=8) or severe (n=2) chronic GvHD was 24±0.4% at one year after HSCT and did not differ between both arms. There was no evidence of impaired immune reconstitution. To date, median OS and DFS have not been reached after a median follow up of 22 months (range, 6-57). At two years after HSCT, 5 patients have died from relapse (n=3), sepsis (n=1) or sudden death (n=1 at 3.5 months after study discontinuation) and CI of relapse was 21±0.5%, resulting in probabilities for 2-year OS and DFS of 88±5% and 74±7%, resp. Discussion: Panobinostat maintenance following HSCT for high-risk AML or MDS is feasible with a RP2D dose of 20 mg TIW weekly or 30 mg TIW every other week and associated with a low relapse rate. This provides a rationale for a prospective randomized trial of panobinostat as post-transplant intervention. Disclosures Bug: NordMedica: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Travel grants, Research Funding; Novartis Oncology: Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Astellas: Other: Travel grant; TEVA Oncology: Other: Travel grant; Gilead: Honoraria. Off Label Use: Panobinostat has not been approved for maintenance therapy after an allogeneic stem cell transplantation in ANL and MDS patients . Burchert:Bristol Myers Squibb: Honoraria. Bader:Neovii: Other: Institutional grants; Medac: Other: Institutional grants; Amgen: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Riemser: Other: Institutional grants. Ottmann:Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: 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; Pfizer: Consultancy, 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.

The purpose of this study is to estimate the fiscal requirements for AI digital textbook subscriptions, which will be introduced with a subscription-based pricing model from 2025 to 2028, and to forecast the burden on local education finance for provincial and municipal education offices. It also aims to present policy considerations regarding future funding allocation that should be taken into account in legislative decision-making. Based on the 2025-2028 schedule for AI digital textbook implementation announced by the Ministry of Education in June 2023, the number of students by grade, and the set price ranges, the results show that applying Scenario S1-1 (an average monthly subscription fee of 5,000 KRW with a 12-month subscription for semester-based textbooks) would require a total of 4.7255 trillion KRW in student subscription fees over four years. Furthermore, it is expected that the fiscal requirements will range from 1.9252 trillion KRW under the minimum scenario (S2-2) to 6.6156 trillion KRW under the maximum scenario (S1-3). Given that the introduction of AI digital textbooks will significantly increase local education finance burdens due to the substantial fiscal requirements involved, potentially causing major changes in the existing textbook system, it is deemed appropriate that this initiative be pursued based on prompt and clear legislative decisions by the National Assembly under the principle of the rule of law for education systems as stipulated in the Constitution of the Republic of Korea. When these premises are clear, the following funding options can be considered: ① extending the effective period or removing the sunset clause for special grants that increase national support for high school tuition-free policies, including textbook costs, ② abolishing the temporary special grant system for digital education innovation needs to secure additional ordinary grant funding, ③ inducing investment from the central government’s general budget to secure additional funding for AI digital textbooks, and ④ utilizing temporary national project special grants in 2025.