How to determine the maximum tolerated dose (MTD) is the primary objective in phase I clinical trial. The study indicates that the trial would fail, largely because a suboptimal dose is recommended to the further stage. The overly toxic dose assigned to patients during the treatment could lead to irreversible damage and even death, as a result, the safety of the design has been frequently emphasized. We propose a novel hybrid design that incorporates the CRM into the Keyboard design. The hybrid design has superiorities in safety control and accuracy of recommendation over the existing designs. The R code for the implementation of the proposed design is provided when needed. The hybrid design maximizes the merits and minimizes the limitations. In other words, the proposed the method possesses these two advantages, the overdose control and full use of information, meanwhile, the aggressive dose transitions of the CRM have been avoided.

There is a strong need for efficient, user-friendly keyboard layouts, especially for languages with extensive character sets such as Hindi. Current Hindi keyboard layouts often require users to remember complex key combinations and do not always follow the logical grammatical sequences of Hindi itself. Rather, they are based on the QWERTY keyboard layout. This article introduces the concept design of a novel Hindi keyboard layout designed based on the phonetics of the Hindi language. This concept design has implications for creating Phonetic keyboards that can have a marked impact on how Hindi language interaction is conducted, especially on mobile phones. In addition, an alternative keyboard is also created based on insights derived from genetic algorithms and compared with the phonetic keyboard. The preliminary comparison of these keyboards indicates implications for the design of Hindi keyboards and for expanding them to support additional Indian languages.

Acoustic Side-Channel Attacks (ASCAs) exploit the sound produced by keyboards and other devices to infer sensitive information without breaching software or network defenses. Recent advances in deep learning, large language models, and signal processing have greatly expanded the feasibility and accuracy of these attacks. To clarify the evolving threat landscape, this survey systematically reviews ASCA research published between January 2020 and February 2025. We categorize modern ASCA methods into three levels of text reconstruction—individual keystrokes, short text (words/phrases), and long-text regeneration— and analyze the signal processing, machine learning, and language-model decoding techniques that enable them. We also evaluate how environmental factors such as microphone placement, ambient noise, and keyboard design influence attack performance, and we examine the challenges of generalizing laboratory-trained models to real-world settings. This survey makes three primary contributions: (1) it provides the first structured taxonomy of ASCAs based on text generation granularity and decoding methodology; (2) it synthesizes cross-study evidence on environmental and hardware factors that fundamentally shape ASCA performance; and (3) it consolidates emerging countermeasures, including Generative Adversarial Network-based noise masking, cryptographic defenses, and environmental mitigation, while identifying open research gaps and future threats posed by voice-enabled IoT and prospective quantum side-channels. Together, these insights underscore the need for interdisciplinary, multi-layered defenses against rapidly advancing ASCA techniques.

Abstract: The BCI (brain-computer interface) speller system comprises essential components,including hardware for recording brain signals and software for processing these signals. EEG(Electroencephalography) sensors record brain activity, which is then analyzed to classify intospecific commands for character selection by the software. The software’s GUI (Graphical UserInterface) facilitates user interaction by displaying the necessary symbols.This article focuses on the design of a virtual keyboard interface aimed at efficiently selectingVietnamese characters for text composition in the BCI spleller system. Our contributions include amulti-layered keyboard design, where keys are organized based on functional groups and thefrequency of character usage in Vietnamese. The multiple layered keyboard features keys thatrepresent individual Vietnamese character, groups of related characters, or functional keys forspecific editing tasks.In our Vietnamese BCI speller system, EEG signals are captured using the EPOC Flex. DuringEEG signal processing, we employ a Linear Discriminant Analysis (LDA) classifier with motorimagery tasks involving right-hand and foot movements. Experimental results with our virtualkeyboard interface indicate that without suggestions, the typing rate achieved was 2.37characters/min, which improved to 6.15 characters/min when suggestions were utilized,demonstrating the effectiveness of our design.Keywords: BCI Speller, Virtual keyboard, Vietnamese keyboard.

A first-in-human phase 1 Study of cbx-250, a TCR-mimetic bispecific T cell engager targeting CG1/ HLA-a*02:01 in patients with relapsed or refractory AML, HR-MDS, or CMML (CROSSCHECK-001) (Trial in Progress)

Keyboards are one of the most crucial and most used interfaces on the planet. However, they are designed to have an “average” user in mind. This raises questions on whether anthropometric variation, specifically finger length, affects typing efficiency. The purpose of this study was to examine the relationship between middle finger length and typing efficiency, specifically typing speed measured in words per minute (WPM) and accuracy (%). Data were collected through a Google Forms survey from 50 participants, where they measured the length of their middle finger using a ruler and took a standardized one-minute online typing test on a laptop or desktop. Results indicated a moderate positive correlation: longer finger lengths were associated with faster typing speed (r = 0.43) and slightly greater accuracy (r = 0.366). These findings propose that while finger length is not the sole determinant of typing efficiency, it has a measurable impact. From an engineering perspective, this study emphasizes the significance of ergonomics and anthropometrics in keyboard design, supporting the need for more adaptable layouts that reduce fatigue and strain, while enhancing efficiency and performance.

10007 Background: Talazoparib (TAL), a potent PARP inhibitor, demonstrated preclinical activity in Ewing sarcoma when combined with irinotecan (IRN) and temozolomide (TMZ). A phase I study (BMNIRN, NCT02392793) showed clinical benefit of TAL + IRN + TMZ; but dose escalation was limited due to hematologic and gastrointestinal toxicity. We therefore evaluated, for the first time in children, nanoliposomal irinotecan (nal-IRI) in combination with either TAL or TMZ. Methods: Patients (pts) aged 1-30 with recurrent or refractory solid tumors were eligible to receive nal-IRI + TAL (Arm A) or nal-IRI + TMZ (Arm B) using a Bayesian keyboard design. Nal-IRI dosage was escalated with fixed TAL and TMZ doses. Each cycle was 21 days. Maximum tolerated dosage(s) (MTD) and recommended phase 2 dosage(s) (RP2D) were determined. Nal-IRI and TAL plasma pharmacokinetics (PK) were evaluated. Toxicities were assessed using CTCAE v.5 and responses were evaluated by RECIST 1.1. UGT1A1 polymorphisms and serial circulating tumor DNA (ctDNA) samples were evaluated. Results: Forty-six pts enrolled at 5 sites. The first 9 (5 Arm A; 4 Arm B) received nal-IRI days 1, 8. Four pts had dose limiting toxicities (DLTs), so day 8 nal-IRI was removed (Amend 1). After Amend 1, 37 pts (23 male; median age 14 years, range 1-23) enrolled (19 Arm A; 18 Arm B). The most common diagnosis was Ewing sarcoma (n = 16, 35%). Table 1 summarizes DLTs in Cycle 1 and response. The most common serious adverse events included febrile neutropenia (12 Arm A; 2 Arm B), colitis (4 Arm A; 2 Arm B), vomiting (4 Arm A), and diarrhea (3 Arm A). Confirmed responses were seen in five Arm A (1 CR, 4 PR) and five Arm B (1 CR, 4 PR) pts with Ewing sarcoma, CIC-DUX4 sarcoma, synovial sarcoma, and rhabdomyosarcoma. Seven pts (5 Arm A; 2 Arm B) had stable disease. Results of PK, UGT1A1 and ctDNA will be presented. Conclusions: The MTDs were nal-IRI 160mg/m 2 plus TAL (Arm A) and nal-IRI 200mg/m 2 plus TMZ (Arm B). The RP2Ds are pending FDA review. These regimens are feasible with evidence of anti-tumor activity and warrant further investigation. Clinical trial information: NCT04901702 . Dose level Nal-IRImg/m 2 IV Arm ANal-IRI + TAL(po, 600mcg/m 2 /dose)Days (D) # of pts Arm BNal-IRI + TMZ(po, 100mg/m 2 )Days (D) # of pts DLT Cycle 1 (# of pts) Confirmed Response(CR, PR, SD, PD) 1 120 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 7 D 1: nal-IRI + TMZD 2-5: TMZ daily 3 Arm A: 1 pt - neutropenia (1) Arm A: CR (1), SD (1), PD (2)Arm B: PR (1), SD (1), PD (1) 2 160 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 10 D 1: nal-IRI + TMZD 2-5: TMZ daily 3 Arm A: 3 pts - anemia (1), thrombocytopenia (1), sepsis (1), colitis (1) Arm A: PR (3), SD (4), PD (3)Arm B: PR (1), PD (1) 3 200 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 2 D 1: nal-IRI + TMZD 2-5: TMZ daily 12 Arm A: 2 pts – abd pain (1), thrombocytopenia (1), neutropenia (1), diarrhea (1)Arm B: 3 pts – nausea (1), neutropenia (1), sepsis (1), thrombocytopenia (1) Arm A: PR (1)Arm B: CR (1), PR (2), SD (1), PD (6)

Pursuing accurate observations and rational assumptions always drives advances in clinical trial design. In recent years, more trials have begun to collect multi-graded outcomes for more informative analyses. At the same time, assumptions other than the traditional monotonicity relationship have been considered in the dose-efficacy curve to be more realistic. Inspired by these two trends, we propose a phase I/II design that simultaneously considers multi-categorical toxicity and efficacy with multi-graded outcomes, measured as quasi-continuous probability based on prespecified weight matrices of clinical significance. Following keyboard design, our approach aims to screen out overly toxic doses by the toxicity probability intervals and adaptively makes dose escalation or de-escalation decisions by comparing the posterior distributions of dose desirability (utility) among the adjacent levels of the current dose. It helps to more accurately identify the OBD in a non-monotonically increasing dose-efficacy relationship. We also comprehensively present the safety, accuracy and reliability performance through numerical simulations in multiple scenarios and compare the results with several already available designs. The benchmarking results of multiple operating characteristics convincingly support that our design leads in overall performance while ensuring robustness.

391 Background: Patients (pts) with high-risk prostate cancer (PCa) have an elevated risk of disease recurrence/progression after definitive therapy. These pts also exhibit increased levels of adrenergic nerve density on PCa histology. Pre-clinical evidence from murine models of PCa suggest that PCaNeurolysis of periprostatic adrenergic nerves inhibits cancer progression and metastasis by inhibiting angiogenesis, altering cancer metabolism, and inhibiting cell migration (PMC5783182). Pure Ethanol (>99%) injection for neurolysis is FDA-approved in chronic cancer pain and may have a survival benefit in late-stage cancers (PMC1242819). Ultrasound-guided (US) short-acting periprostatic neuraxial block with lidocaine is commonplace in urologic practice. Thus, PCaNeurolysis with ethanol may have both a protective effect in high risk PCa and be feasibly implemented. Methods: Pts with NCCN high risk PCa who were interested and eligible for surgery, and who did not have any prior PCa treatments received in-office US guided PCaNeurolysis with either 3mL or 5mL of pure ethanol 4 to 6 weeks prior to radical prostatectomy (surgery was not delayed for trial participation). Dose escalation was determined by keyboard design with 6 pts per group (dose limiting toxicity [DLT] period = 6 weeks; DLT ³ Grade 3 events). Results: Dose escalation: 12 pts, median age 68, were treated at 2 dose levels: 3/5mL (n=6/6) with no DLTs in either group, suggesting 5mL was maximal tolerated dose to use in future studies. Additionally, no off-target effects including no decrease in erectile function (Sexual Health Inventory for Men score), no increase in urinary symptoms (International Prostate Symptom Score), and no added difficulty (eg. Destruction of tissue planes) during prostatectomy were observed in any pts. 7 pts underwent prostatectomy (43% cT3a) and were included in secondary analysis: median decrease in adrenergic density on final pathology (35%), ≥pT3a (0%), 18month biochemical recurrence (14%). Conclusions: PCaNeurolysis with ethanol was well tolerated, and 5mL was the maximum tolerated dose to use in future studies. Histologically significant decrease in adrenergic nerve density was observed suggesting the intervention acts upon its intended target, and the intervention may have antitumor activity (43% pre-injection cT3a, but 0% ≥pT3a on final pathology after injection). These Phase 1 results encourage continued investigation of PCaNeurolysis in high risk PCa pts.

A Phase I Study to Evaluate the Safety and Tolerability of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination with Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia

Abstract Background: How to determine the maximum tolerated dose (MTD) is the primary objective in phase I clinical trial. The study indicates that the trial would fail, largely because a suboptimal dose is recommended to the further stage. The overly toxic dose assigned to patients during the treatment could lead to irreversible damage and even death, as a result, the safety of the design has been frequently emphasized. Methods: We propose a novel hybrid design that incorporates the CRM into the Keyboard design. Results: The hybrid design has superiorities in safety control and accuracy of recommendation over the existing designs. Conclusion: The hybrid design maximizes the merits and minimizes the limitations. In other words, the proposed the method possesses these two advantages, the overdose control and full use of information, meanwhile, the aggressive dose transition of the CRM has been avoided.

Investigating the effect of key size, typing angle, and typing technique of virtual keyboard on typing productivity, biomechanics, and usability in a mixed reality environment

Conventionally, dose finding trials are based on dose-limiting toxicity (DLT) that only captures the most severe toxicities, for example, treatment related grade 3 or higher toxicity according to the NCI Common Terminology Criteria for Adverse Events. However, this approach is often problematic for certain novel targeted therapies and immunotherapies, which may not induce DLT within a clinically active dose range and are often characterized by low grade toxicities. This important issue has been highlighted and discussed in the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forums, and is also an important consideration of the Project Optimus initiated by FDA to “reform the dose optimization and dose selection paradigm in oncology drug development.” In this article, we propose an easy-to-implement model-assisted Bayesian design, known as multiple toxicity keyboard (MT-Keyboard) design, to incorporate toxicity grades and types into dose finding. The MT-Keyboard design is able to accommodate binary, quasi-binary and continuous toxicity endpoints that are constructed to account for toxicity grades and types. We further extend the MT-Keyboard design, referred to as TITE-MT-Keyboard, to accommodate late-onset toxicity using the approximated likelihood approach. Simulation shows that the MT-Keyboard and TITE-MT-Keyboard designs have desirable operating characteristics, comparable to or better than some existing designs. A web-based software to implement the design will be freely available at www.trialdesign.org. Supplementary materials for this article are available online.

Design and evaluation of alphabetic and numeric input methods for virtual reality

Abstract Background AKT pathway activation is implicated in endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance in patients (pts) with HR+/HER2– advanced breast cancer (ABC). In CAPItello-291, capivasertib (C, a potent inhibitor of all 3 AKT isoforms) + fulvestrant (F) significantly improved PFS versus placebo F in pts with aromatase inhibitor-resistant HR+/HER2– ABC. Simultaneous inhibition of AKT and CDK4/6 pathways may delay CDK4/6i resistance or re-sensitize tumors to ET plus CDK4/6i, leading to improved clinical outcomes. CAPItello-292 (NCT04862663) is an ongoing Phase 1b/3 study examining the efficacy and safety of C + CDK4/6i (palbociclib [P], ribociclib [R]) + F in HR+/HER2– ABC. The recommended Phase 3 dose (RP3D) of C+P+F has been determined (C 400 mg BID, 4 days on/3 days off, P 125 mg, F 500 mg). Here we report ongoing Phase 1b data on C+P+F and C+R+F. Methods: Phase 1b of CAPItello-292 uses a keyboard design (mTPI-2) with the following planned doses: C 200 mg, 320 mg, 400 mg; P 75 mg, 100 mg, 125 mg; R 200 mg, 400 mg, 600 mg; F is fixed at 500 mg every 28 days + loading dose on cycle 1 day 15. Starting doses for C+P+F were C 320 mg BID, 4 days on/3 days off, P 125 mg QD) for 21 days of each 28-day cycle. Starting doses for C+R+F (ongoing) are C 400 mg BID, 4 days on/3 days off, R 400 mg QD for 21 days of each 28-day cycle. Eligible pts have HR+/HER2− ABC and ≥1 prior ET in the advanced setting or disease recurrence within 12 months of completing (neo)adjuvant ET (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative). Prior use of CDK4/6i, selective estrogen receptor degraders, and chemotherapy is permitted in Phase 1b. Phase 1b primary objectives: assess safety/tolerability; confirm RP3D. Objective response and clinical benefit rates (24 weeks; RECIST v1.1) were also assessed. Results: At data cut-off (Apr 21, 2023), 40 pts (median age: 58.5 years [range 38–82]) who were heavily pre-treated (as follows: 82.5% [33/40] prior CDK4/6i; 47.5% [19/40] prior F; 70.0% [28/40] prior chemotherapy [median 1.5 lines]) were treated with C+P+F. No new dose-limiting toxicities (DLTs) were observed since determination of RP3D. The most frequent adverse events (AEs) occurring in >40% of pts were diarrhea (70.0% [28/40]; 1/28 grade [G] ≥3), neutropenia (55.0% [22/40]; 20/22 G≥3), fatigue, and nausea (both 42.5% [17/40]; all G1/2). Hyperglycemia occurred in 17.5% (7/40) pts (1/7 G3). No treatment-related deaths or new safety risks were identified. At the RP3D, the median (range) duration of exposure to C was 8.6 months (1.7–14.1); 5/8 pts with measurable disease at baseline had confirmed partial response (objective response rate: 62.5%, 95% confidence interval [CI] 24.5–91.5). Two additional pts had stable disease ≥7 weeks as a best objective response. At 24 weeks, the clinical benefit rate was 53.8% (7/13; 95% CI 25.1–80.8).Enrollment into C+R+F is ongoing: as of May 05, 2023, 8 pts had been dosed (6/8 pts had completed cycle 1). Based on clinical and safety review, the safety review committee has endorsed dose escalation to the highest dose level of R; no DLTs have been reported so far, although data are preliminary.Preliminary ctDNA analyses of pts treated with C+P/R+F will be presented. Conclusions: C+P+F was tolerable in heavily pre-treated pts with HR+/HER2– ABC at all dose levels; AEs were as expected, given the known safety profile of the individual treatments. Evidence of clinical activity has been observed in pts treated with the RP3D; data collection is ongoing. Preliminary safety analysis of C+R+F suggests no critical tolerability concerns; more pts and longer follow-up is required to characterize the safety of the combination. Updated data will be presented. Funding: AstraZeneca Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited) Citation Format: Erika Hamilton, Patrick Neven, Barbara Pistilli, Muralidhar Beeram, Virginia Borges, Mario Campone, José Luiz Miranda Guimarães, Theodoros Foukakis, Annette Raskov Kodahl, Peter Lau, Elgene Lim, Iwona Ługowska, Greg Rychlik, Christopher Gresty, Claire Miller, Roberto Sommavilla, Dhivya Sudhan, Hope Rugo. Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-09.

TPS713 Background: PDAC is characterized by its innate and acquired resistance to both MAPK pathway inhibition and immune checkpoint (e.g. PD-1/PD-L1) inhibition (ICI) via multiple mechanisms. In preclinical models of PDAC, combined MEK and STAT3 inhibition (MEKi+STAT3i) uncovers stromal plasticity by attenuating cancer-associated fibroblasts (CAF) with IL-6/CXCL1-secretory phenotypes while enriching for Ly6a/CD34-expressing CAF phenotypes with mesenchymal stem cell-like features. This remodeling of CAF heterogeneity is associated with a striking attenuation in and reprogramming of tumor-associated macrophages (TAMs) as well as enhanced trafficking of CD8 T cells, which exhibit a distinct effector and anti-apoptotic transcriptional program. The addition of MEKi+STAT3i to PD-1 blockade overcomes ICI resistance by significantly enhancing the recruitment, degranulating capacity, and functional cytotoxicity of CD8+ T-cells, thereby augmenting antitumor responses and dramatically improving survival in these models. Furthermore, a patient with refractory PDAC treated off-label with this combination achieved a meaningful response. Based on this strong rationale, a phase 1 trial was initiated to test the combination of MEKi+STAT3 and PD1 inhibition in patients with metastatic PDAC. Methods: NCT05440942 is an open-label, prospective, single-institution phase 1 trial testing the safety, preliminary efficacy, and biomarkers of response to the combination of trametinib (MEKi), ruxolitinib (JAK2/STAT3 inhibitor) and retifanlimab (PD-1 inhibitor) in patients with metastatic PDAC. Patients with metastatic PDAC who have had disease progression on at least one line of prior therapy, with good organ function, preserved performance status, and without major intercurrent illness are eligible. Patients must have an accessible lesion for biopsy and must be willing to undergo this research biopsy at baseline and on treatment. Part 1 of the study is a dose-escalation phase with 3 dose levels and a target dose of trametinib 2mg orally daily, ruxolitinib 15mg orally twice daily, and retifanlimab 500mg intravenously every 28 days. The dose escalation is being done using the novel Bayesian keyboard design and 9-15 patients will be treated to get to the potential maximum tolerated dose (MTD). Dose level 1 has been completed without any dose-limiting toxicities seen. Part 2 is an expansion phase which will accrue an additional 20 patients. All patients in part 1 and 2 will have core-needle biopsies pre-treatment and after 4 weeks. Serial blood samples will be collected at baseline and on treatment. Biopsies are being analyzed by multiparameter immune profiling using mass cytometry and bulk RNA sequencing; blood is being analyzed for circulating tumor DNA and immune profiling. These results will be correlated with clinical response to therapy to determine biomarkers of response and resistance. Clinical trial information: NCT05440942 .

Coronado CLL: A Phase Ib/II Trial of Combination Rp-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refract ory Chronic Lymphocytic Leukemia

Zegocractin to Reduce the Severity of Asparaginase Associated Pancreatitis in Children with Acute Lymphoblastic Leukemia: Results of the Phase 1 Portion of the Crspa Study

This study aims to explore the current status and analysis of mouse and keyboard ergonomic design products. For mice and keyboards, explain the current status of their products, analyze their problems and propose solutions through the current widely used mice and keyboards, and look forward to their future development trends. Through this research, we can better understand the current state of ergonomic design of mice and keyboards, analyze their strengths and weaknesses, and provide ideas and directions for future design. This study has certain practical significance for improving the human-computer interaction experience of mouse and keyboard products.

Usability of curved keyboard design on the large smartphone: An empirical study