Key Criteria Research Articles

RTID-06. THE PIVOTAL METIS (EF-25) STUDY OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC) FOLLOWING RADIOSURGERY

Abstract INTRODUCTION: TTFields are electric fields that disrupt processes necessary for cancer cell survival and can stimulate an antitumor immune response in preclinical NSCLC models. TTFields therapy is a noninvasive and locoregional treatment approved for glioblastoma, which has recently demonstrated a survival benefit when applied to the thorax with standard of care (SOC) systemic therapy in patients with metastatic NSCLC that progressed on/after platinum. Here we describe the pivotal METIS study (EF-25, NCT02831959) evaluating the efficacy and safety of TTFields therapy applied to brain metastases from NSCLC. TRIAL DESIGN: Patients (270) with 1–10 brain metastases from NSCLC will receive stereotactic radiosurgery (SRS), followed by 1:1 randomization to TTFields (NovoTTF-200M [150 kHz] applied to the head ≥ 18 h/day) with best SOC, or best SOC alone. Key inclusion criteria are life expectancy ≥ 3 months, a new diagnosis of 1 inoperable or 2–10 supra and/or infratentorial brain metastases from NSCLC, that are amenable to SRS. Patients who had prior whole brain radiotherapy, or have single operable, leptomeningeal, or recurrent brain metastases, certain genetic mutations, or severe comorbidities or contraindications, are not eligible. The primary endpoint is time to first intracranial progression. Secondary endpoints include time to neurocognitive failure, overall survival, radiological response rate, time to second intracranial progression, time to first/second intracranial progression by modified RECIST v1.1, rate of intracranial progression, time to distant progression, rate of cognitive decline, quality of life, neurocognitive failure-free survival, and safety. The study is powered at 80% (2-sided alpha of 0.05) to detect a hazard ratio of 0.57. In July 2021, an independent Data Monitoring Committee reviewed the study data and recommended continuation. The study includes 128 sites in Europe, Israel, mainland China, North America, and Hong Kong. The final patient was enrolled in March 2023.

RTID-03. A PHASE 1/2 STUDY OF THE WEE1 INHIBITOR DEBIO 0123 IN COMBINATION WITH TEMOZOLOMIDE +- RADIOTHERAPY IN ADULTS WITH RECURRENT OR NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle checkpoint abrogation, permitting mitosis without DNA repair, leading to mitotic catastrophe and subsequent cell death. Preclinically, Debio 0123 has been shown to effectively penetrate the brain and demonstrated improved response to radiotherapy (RT) in vitro and temozolomide (TMZ) in mouse models of GBM, supporting the clinical investigation of Debio 0123 with TMZ +/- RT. Trial design: This Phase 1/2 multi-center study (NCT05765812) is evaluating Debio 0123 in combination with TMZ in patients (pts) with recurrent GBM isocitrate dehydrogenase (IDH)-wildtype (WT) or astrocytoma, IDH-mutant, Grade 3 (per WHO 2021 criteria) after first-line, TMZ-based chemoradiotherapy (CxRT) (Phase 1 Arm A) and Debio 0123 combined with TMZ-based CxRT in pts with newly diagnosed GBM IDH-WT (Phase 1 Arm B). In Arm A, pts will receive escalating doses of Debio 0123 with TMZ in 28-day cycles supported by a Bayesian logistic regression model (BLRM). Arm B is a Debio 0123 dose escalation with concomitant TMZ/RT for up to 6 weeks. The primary objective of both Phase 1 arms is to identify the recommended Phase 2 dose (RP2D). Secondary objectives include safety, pharmacokinetics, and preliminary antitumor activity. Key inclusion criteria are ≤2 prior treatment lines (only 1 systemic line allowed) and Karnofsky Performance Status (KPS) ≥60 (Phase 1 Arm A). In Phase 1 Arm B, pts with KPS ≥70 who are eligible for standard TMZ-based CxRT will be included. Phase 2 will be an externally controlled, open-label study comparing the efficacy (overall survival) of Debio 0123 combined with TMZ at the Phase 1 Arm A RP2D vs. standard of care in pts with recurrent GBM IDH-WT. The control arm will include patient-level data from recently completed clinical trials. Accrual is currently ongoing.

LTBK-09. RESULTS OF BMX-HGG STUDY: A MULTI-INSTITUTIONAL, RANDOMIZED PHASE 2 CLINICAL TRIAL OF CONCURRENT CHEMORADIATION WITH OR WITHOUT BMX-001 IN PATIENTS WITH NEWLY DIAGNOSED HIGH GRADE GLIOMA

Abstract BACKGROUND Standard treatment for high grade glioma (HGG) remains neurosurgical resection followed by concurrent radiation therapy (RT) and temozolomide (TMZ). Overall survival (OS) for GBM is roughly 12-16 months. RT is associated with cognitive and quality of life (QoL) impairments. Advances are needed to improve OS while mitigating injury to the normal brain. BMX-001 is a novel metalloporphyrin that radiosensitizes cancer cells and radioprotects normal tissue. METHODS This multi-institutional, open-label, phase 2 trial randomized newly diagnosed HGG patients to receive RT/TMZ with or without BMX-001 (NCT02655601). Both arms received 6 weeks RT/TMZ (75 mg/m2). BMX-001 was administered as a loading dose of 28 mg sc before RT, followed by 14 mg twice weekly for 8 weeks. Randomization was stratified by tumor grade and institution. Key eligibility criteria include histologically confirmed HGG, age ≥ 18 years, and KPS ≥ 70%. The primary endpoint was OS. Key secondary/exploratory outcomes included cognition, QoL, and white matter integrity using advanced imaging. OS evaluation occurred after 84 deaths when a 1-tailed logrank test (α=0.2) had 90% power to detect a hazard ratio of 0.63. Two interim analyses and a final analysis were conducted using an O’Brien-Fleming stopping boundary. RESULTS Of the 160 patients randomized, 72.5% had GBM, and 62.5% were male. Analyses focused on 145 patients who completed RT/TMZ (74 with BMX-001, 71 without BMX-001). Median OS of BMX-001+RT/TMZ group (31.3 [95% CI, 21.6, not reached] months) was longer than RT/TMZ group (24.7 [95% CI, 19.6-32.6] months), HR=0.735; p=0.079 (significant at the predefined α level). Common toxicities (Grade 1-2) attributed to BMX-001 were injection site reactions (64), tachycardia (24), and pruritus (17) with no related Grade 4-5. Diffusion tensor MR imaging indicated mitigation of dose-related white matter damage in BMX-001+RT/TMZ group. CONCLUSIONS BMX-001 is safe, and there is improved OS in HGG patients receiving BMX-001.

CTNI-67. FIRST IN HUMAN STUDY OF DSP-0390, AN ORAL EMOPAMIL BINDING PROTEIN (EBP) INHIBITOR, IN RECURRENT HIGH-GRADE GLIOMA (HGG): PRELIMINARY RESULTS

Abstract BACKGROUND Cholesterol in the brain is derived wholly from de novo biosynthesis as the blood-brain barrier prevents uptake from the circulation. The overexpression of cholesterol synthesis genes is associated with decreased survival in glioblastoma (GBM), suggesting that gliomas may be sensitive to the inhibition of cholesterol biosynthesis. DSP-0390 is an investigational small molecule that inhibits EBP, a key enzyme in cholesterol biosynthesis. Preclinical studies demonstrated antitumor activity of DSP-0390 in orthotopic xenograft GBM models. METHODS This phase I dose escalation study aims to assess the safety, PK, PD, and preliminary antitumor activity of oral DSP-0390 monotherapy for recurrent HGG (NCT05023551). Key eligibility criteria include histologically confirmed grade III or IV glioma (WHO 2016); treatment with ≥ 1 prior therapy; no treatment options beyond standard of care; KPS ≥ 70. RESULTS As of 9 May 2023, 24 patients (37.5% women) were enrolled across 6 dose levels (20 mg QD to 240 mg QD) with a median age of 51 years (range 24-76) including 17 (70.8 %) with GBM, 3 (12.5%) with anaplastic astrocytoma and 2 (8.3%) with anaplastic oligodendroglioma. Ten patients (41.7%) had IDH mutant tumors. Four patients (16.7%) were on stable dose of corticosteroids at baseline, of which 2 were able to discontinue or dose reduce the corticosteroid while on DSP-0390. There were no reported DLTs. The most common treatment-related TEAEs included grade 1 or 2 nausea (7 patients [29.2%]) and alanine aminotransferase increased (6 patients [25.0%]). Only one grade 3 related AE (dry skin) was noted. Two patients with IDH mutant grade 3 glioma had tumor reduction and remain on DSP-0390 for ≥ 9 months. Dose dependent changes in PK and PD were observed. CONCLUSIONS DSP-0390 has been well tolerated to date with dose escalation ongoing. A dose response relationship was observed between PK and PD biomarkers.

Trends in newly diagnosed atrial fibrillation and oral anticoagulant use after cardiac surgery: a population-based analysis from Ontario, Canada

Abstract Background Post-operative atrial fibrillation after cardiac surgery is associated with an increased risk of death and ischemic cardiovascular outcomes. In the non-surgical setting, oral anticoagulation (OAC) is beneficial among patients with AF in reducing their risk of thromboembolism. The use of OAC for patients with post-operative AF after cardiac surgery is not well-defined in contemporary clinical practice - at a time when direct oral anticoagulants (DOAC) are commonly prescribed in the non-surgical setting. Purpose To examine trends in OAC use among patients with post-operative atrial fibrillation after cardiac surgery at a time when DOAC is commonly prescribed in clinical practice. Methods The study cohort consisted of consecutive patients (>65 years) who experienced post-operative AF within 90 days after coronary artery bypass grafting (CABG), isolated left-sided non-mechanical heart valve surgery (iValve), and combined CABG + valve surgery between 2008 and 2021, identified by a mandatory provincial registry of all patients undergoing cardiac surgery in Ontario, Canada. Key exclusion criteria included: patients with pre-existing AF, end-stage renal disease requiring dialysis, mechanical heart valves, left atrial appendage ligation, and those who required anticoagulation for non-AF indications. Prescription of OAC (warfarin or DOAC) within 90 days after discharge from surgery was collected via linkage with the Ontario Drug Benefits Plan. Results The overall cohort consisted of 45,571 patients, in whom 14,572 (32.0%) developed POAF after cardiac surgery. Rates of POAF were highest among patients who underwent combined CABG + valve surgery (44.3% in 2008 to 34.2% in 2021), followed by iValve (42.6% in 2008 to 37.3% in 2021), then followed by isolated CABG (27.6% in 2008 to 24.2% in 2021). Over the study period, there was a decrease in the rates of POAF among patients who underwent all three types of cardiac surgery (P[trend] <0.01). In 2021, rates of oral anticoagulation were highest among patients who underwent combined CABG + valve surgery (61.1%), followed by iValve (59.2%) and isolated CABG (42.0%). Among patients who underwent isolated CABG, there was a 9% increase in the rates of OAC use during the study period (P[trend] <0.001). On the other hand, rates of OAC use remained largely unchanged (Figure A) among patients who underwent iValve and combined CABG + valve surgery (P[trend] 0.24 and 0.26, respectively). Since 2018, DOAC accounted for 60-70% of all OAC prescriptions (Figure B). Conclusions Despite advances in surgical techniques and post-operative care, the rates of post-operative atrial fibrillation after cardiac surgery remain substantial. Prescription rates for OAC remain modest over the past decade, but DOAC is increasingly more commonly prescribed in this patient population. Randomized trials are needed to assess the risks and benefits of OAC, specifically DOAC, in this high-risk patient population.Figure AFigure B

Validation and potential usefulness of the updated PROMISE minimal risk tool in patients with suspected coronary artery disease undergoing coronary CT angiography

Abstract Introduction The steady decline in test positivity among patients with suspected coronary artery disease (CAD) has raised interest in developing strategies to identify patients who may not require testing. The updated PROMISE minimal-risk tool (PMRT) was developed specifically for this purpose, but never tested in our population. The aim of this study was to assess the diagnostic performance of this new tool, and to compare it with the guideline-recommended pre-test probability (PTP) and with the risk factor-weighted clinical likelihood (RF-CL) model in a Portuguese cohort of symptomatic patients undergoing coronary computed tomography angiography (CCTA). Methods We conducted a two-centre cross-sectional study of symptomatic patients undergoing CCTA for suspected CAD. Key exclusion criteria were age <30 years, known CAD, suspected acute coronary syndrome or symptoms other than chest pain or dyspnoea. A simplified version of the updated PMRT (without HDL-C), the guideline PTP, and RF-CL score were calculated for each patient. Obstructive CAD was defined as any luminal stenosis ≥ 50% on CCTA. ‘Low risk’ was defined as absence of obstructive CAD and coronary artery calcium (CAC) score < 100 (both conditions present, where CCTA results are unlikely to change patient management). The cut-off value of the PMRT with 95% positive predictive value for identifying patients with ‘Low risk’ was identified in ROC curve analysis. Results A total of 2162 patients (mean age 60±11years, 59% female) were included. Overall, 14.9% (N=323) of patients had obstructive CAD, and 73.5% (N=1589) fulfilled the criteria for ‘Low risk’. Patients with ‘Low risk’ were more frequently female, had higher prevalence of non-anginal chest pain and had fewer cardiovascular risk factors. For obstructive CAD, the discriminative power of the updated PMRT was similar to the one provided by the guideline PTP and RF-CL models (Figure 1A). However, for identifying patients with ‘Low risk’, the updated PMRT showed greater discriminative power than the guideline PTP and RF-CL models (Figure1B). The PMRT cut-off value with 95% positive predictive value for detecting patients at "Low risk" was identified as >46%. A total of 458 patients (21.2%) had a PMRT >46%. Conclusion In this cohort of symptomatic patients undergoing CCTA, the updated PMRT showed similar discriminative power for obstructive CAD, but greater discriminative power to identify "Low risk" than the guideline-recommended PTP and the RF-CL models. The criterion that identified "Low Risk" with 95% positive predictive value was present in roughly one fifth of patients undergoing CCTA, who would derive less benefit from testing.

Menopausal vasomotor symptoms and plasma Alzheimer disease biomarkers

BackgroundIdentifying risk factors for Alzheimer’s disease (AD) in women is important as women comprise two thirds of individuals with AD. Prior work links vasomotor symptoms (VMS), the cardinal menopausal symptom, with poor memory performance and with alterations in brain structure, function, and connectivity. These association are evident when VMS are monitored objectively with ambulatory skin conductance monitors. ObjectiveTo determine whether VMS are associated with AD biomarkers. Study DesignBetween 2017 and 2020 the MsBrain study enrolled 274 community-dwelling women aged 45-67 who had a uterus and at least one ovary and were late perimenopausal or postmenopausal. Key exclusion criteria included neurological disorder, surgical menopause, and recent use of hormonal or non-hormonal VMS treatment. Women underwent 24 hours of ambulatory skin conductance monitoring to assess VMS. Plasma concentrations of AD biomarkers including amyloid β (Aβ) 42/40 ratio, phosphorylated tau (p-tau 181 and 231), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were measured using single molecule array (Simoa) technology. Associations between VMS and AD biomarkers were assessed via linear regression models adjusted for age, race/ethnicity, education, body mass index, apolipoprotein E4 status, and in additional models, estradiol and sleep. ResultsA total of 248 (mean age=59.06 years, 81% white, 99% postmenopausal) of enrolled MsBrain participants contributed data. Objectively-assessed VMS occurring during sleep were associated with significantly lower Aβ42/Aβ40, [B(SE)=-.0010 (.0004), p=.018, multivariable], suggestive of greater brain Aβ pathology. Findings remained significant after additional adjustments for estradiol and sleep. ConclusionsNighttime VMS may be a marker of women at risk of AD. It is yet unknown if these associations are causal.

Abstract 18221: Interleukin-6 in Patients With HFrEF and the Effect of Dapagliflozin: Insights From DAPA-HF

Introduction: Inflammation plays an important pathophysiological role in the development and progression of heart failure (HF). Interleukin-6 (IL-6) is a circulating cytokine which is the main regulator of the release of C-reactive protein (CRP) along with pro-inflammatory cytokines. It has been suggested that one of the potential mechanisms of action of sodium glucose co-transporter 2 (SGLT2) inhibitors may be to reduce inflammation. We examined the association between IL-6 and outcomes in patients with HF with reduced ejection fraction (HFrEF) in the DAPA-HF trial and its relationship with the effect of dapagliflozin. Methods: Key inclusion criteria were: 1) NYHA class II-IV, 2) LVEF ≤40%, 3) elevated NT-proBNP and 4) eGFR ≥30 ml/min/1.73m 2 . The primary outcome was a composite of a first episode of worsening HF or cardiovascular death. IL-6 (Roche Diagnostics, e411) was measured at baseline and 52 weeks. Results: Median (IQR) baseline IL-6 was 6.01 pg/mL (interquartile range 4.18-9.29) in the 2980/4774 with available data. Baseline IL-6 quartiles were: Q1 ≤4.18 pg/mL, Q2 4.19-6.01 pg/mL, Q3 16.02-9.29 pg/mL, Q4 ≥9.3 pg/mL. Median high-sensitivity CRP at baseline was 1.13 mg/L and 3.78 mg/L in those with an IL-6 level < or ≥ the median, respectively. The adjusted risk of the primary outcome relative to Q1 was: Q2 = HR 1.39 (95%CI 1.02, 1.89), Q3 = HR 1.55 (1.15, 2.08), Q4 = 2.07 (1.55, 2.76) ( Fig A ). The beneficial effect of dapagliflozin compared with placebo was consistent whether IL-6 was analysed in quartiles (P int = 0.77) or as a continuous variable (P int = 0.69 [ Fig B ]). The placebo-corrected relative change in IL-6 at 52 weeks was -4.1% (95%CI -9.1, +1.2), p=0.13. Conclusions: In DAPA-HF, elevated IL-6 levels were an independent predictor of the risk of cardiovascular death or worsening HF. Dapagliflozin reduced the risk of cardiovascular death or worsening HF regardless of baseline IL-6.

Abstract 15115: Efficacy and Safety of miR-132 Inhibitor CDR132L in Patients With Reduced Left Ventricular Ejection Fraction After Myocardial Infarction: Rationale for and Design of the HF-REVERT Trial

Background: Inhibition of miR-132 effectively prevents and reverses heart failure (HF) in relevant models, making it an attractive HF target. CDR132L is a synthetic antisense oligonucleotide (ASO) selectively blocking miR-132. Translational in vitro and in vivo studies have demonstrated meaningful efficacy of CDR132L on left ventricular (LV) structure and function. CDR132L was safe and well tolerated in a Phase 1b study in chronic HF patients. The indicative effects of the miR-132 inhibitor CDR132L may be particularly beneficial in patients with active adverse remodelling, e.g. after acute myocardial infarction with early decline in ejection fraction. These patients have been relatively understudied and therapeutic options are limited. Method: The HF-REVERT (P h ase 2, Multicenter, Randomized, Parallel, 3-arm, Placebo-controlled Study to Assess E f ficacy and Safety of CD R 132L in Pati e nts with Reduced Left V entricular E jection F r ac t ion (≤ 45%) after Myocardial Infarction; NCT05350969) is a proof-of-concept study to evaluate the efficacy of CDR132L in improving cardiac function and safety in patients with reduced LV ejection fraction (LVEF). HF-REVERT aims to assess the efficacy and safety of 5 mg/kg and 10 mg/kg CDR132L, given as 3 single intravenous doses administered 28 days apart as an add-on to standard-of-care treatment, in a larger cohort of patients (N = 280) with HF and reduced LVEF (≤ 45%) after MI with a follow-up of 10 months. Key inclusion criteria are the diagnosis of acute STEMI/NSTEMI and the development of systolic dysfunction (LVEF ≤ 45%) after MI index event and elevated N-terminal pro B-type natriuretic peptide (NT-proBNP). The study consists of a 6-month double-blind treatment period with a read out of the primary endpoint LVESVI (left ventricular end systolic volume index) followed by a 6-month open label observation period. Discussion: The HF-REVERT trial currently tests CDR132L in patients with MI and systolic dysfunction. This trial may therefore underpin the concept of miR-132 inhibition to prevent/reverse cardiac remodeling in HF patients. The results will inform the design of a subsequent outcome trial to test the effect of CDR132L in HF patients.

Spatial preferences of small and medium knowledge based enterprises in Tehran new business area

In recent decades, there has been a growing emphasis on the importance of small and medium-sized enterprises (SMEs) as a significant driver of economic growth and enhancer of competitiveness. They constitute an estimated 90% of the total population of businesses, and contribute significantly, up to 40% of Gross Domestic Product (GDP), in emerging markets. Furthermore, these enterprises yield a fundamental function in cultivating job prospects, offering employment to approximately half of the worldwide labor force. However, SMEs often face unique challenges related to their size and resources, including accessing finance, developing new products and services, and identifying optimal locations for their businesses. This study seeks to address the latter issue by analyzing the spatial preferences of small and medium knowledge-based enterprises in Tehran's new business area, utilizing the spatial analyst tools by GIS. The research methodology employed in this study is non-experimental in character. It involves the distribution of a social survey to proprietors of SMEs in order to ascertain the key criteria they prioritize when selecting a location for their business. For the purpose of achieving the objective, a conceptual-operational model was developed, comprising four index categories. These categories are delineated as the personal motivations of the entrepreneur, the characteristics of the internal business environment, the spatial environment surrounding the business, and the institutional factors shaping the space. These components constitute critical determinants of the proposed model. The chosen variables were subjected to spatial analysis, and a business environment assistance map was developed in four zones. Following thorough analysis, the northwestern part of the area under consideration has been identified as the optimal zone, and subsequent recommendations for appropriate strategies have been proposed. The study culminated by offering suggestions for improvement, consisting of the implementation of a contextually-oriented model pertaining to new Iranian business improvement districts (BIDs) as a means of augmenting the status of SMEs.

What is the impact of a multi‐component exercise intervention on the cure rate of urinary incontinence among older women living in the community?

AbstractAimsTo determine the impact of a multi‐component exercise intervention on the cure rate of urinary incontinence (UI) among older women living in the community.MethodA systematic search was conducted of five databases (Medline, Cumulative Index to Nursing and Allied Health Literature [CINAHL], Academic Search Complete, PubMed and Web of Science), grey literature and reference lists of relevant studies in December 2021– January 2022 and again between January 2023 and February 2023 when no additional new studies were identified. Key inclusion criteria were studies with female older adults above the age of 60, with any type of UI, residing in the community, addressing the effects of a multi‐component exercise intervention combining pelvic floor muscle training (PFMT), strength and balance exercises. The primary outcome of interest was the cure rate of UI in community‐dwelling older women (%).Studies underwent quality appraisal using the RevMan Risk of Bias tool and the Evidence‐based Librarianship tool, identifying significant biases. A narrative synthesis presents results for all outcomes; a meta‐analysis was also performed for secondary outcomes.ResultsFollowing the PRISMA 2020 guidelines, a total of 596 records were identified from the systematic search. Five studies met the inclusion criteria. Participants receiving the intervention had a statistically significant mean cure rate of 44.0% (p < 0.05), which decreased at follow‐up, except for participants with stress UI. Participants receiving the intervention had significantly decreased frequency of UI episodes (p < 0.00001) and increased maximum walking speed (p < 0.0003) at a 3‐month follow‐up.ConclusionA multi‐component exercise, combining PFMT, strength and balance exercises, is effective in improving and curing UI, especially stress UI, in community‐dwelling older women.

Jahn-Teller distortion in bis(terpyridine)nickel(III) – Elongation or compression?

DFT methods were used to evaluate the type of Jahn-Teller distortion in the low spin d7 bis(terpyridine)nickel(III) doublet. The strain of the tridentate terpyridine ligand in bis(terpyridine)nickel(III) leads to longer Ni(III)-N terminal bond lengths than the Ni(III)-N central bonds. In addition, in all DFT optimized bis(terpyridine)nickel(III) molecules, the one set of Ni(III)-N terminal bonds are longer than the other set of Ni(III)-N terminal bonds. Three pairs of Ni(III)-N bonds are present in bis(terpyridine)nickel(III), namely 2 longer Ni(III)-Nterminal1 terminal bonds, 2 medium length Ni(III)-Nterminal2 terminal bonds and 2 shorter Ni(III)-Ncentral central bonds, similar to orthorhombic Jahn-Teller distortion in octahedral complexes. Evaluation of bond length differences, contraction of bonds, spin density plots and the character of the singly occupied molecular orbital (SOMO) and singly unoccupied molecular orbital (SUMO), led to a set of criteria to consider in evaluating the type of Jahn-Teller distortion in the low spin d7 bis(terpyridine)nickel(III) doublet. Jahn-Teller distortion can lead to elongation (z-out) or compression (z-in) of a pair of opposite Ni-N bonds. One key criteria found, is, if the difference in bond length between Ni(III)-Nterminal1 and Ni(III)-Nterminal2 is smaller than the difference in bond length of Ni(III)-Nterminal2 and Ni(III)-Ncentral, then it is a Jahn-Teller compression geometry (and vice versa for a Jahn-Teller elongation geometry).

Evaporation and heat exchange of a thin liquid layer under various heating methods: Advantages of local heating over uniform heating of the wall

Intensification of heat transfer and evaporation is widely used in modern technologies at limited dimensions of heat exchange surfaces and high energy density. To date, stationary heat transfer at uniform wall heating, has been most thoroughly investigated. Meanwhile, there is no comprehensive research providing a comparison of free convection, heat transfer and evaporation with different heating methods. The novelty of the work lies in the comparison of the heat transfer efficiency using one laser beam, two beams and homogeneous heating. When heated by a single laser beam, the average temperature of the layer interface is significantly lower than at homogeneous heating. However, due to the generation of intense Marangoni flow, a small heating spot provides more intense evaporation than homogeneous heating. The effectiveness of heat transfer is analyzed in terms of the total efficiency coefficient. If it is important to take into account power input, it is preferable to use a single laser beam. If it is not decisive, then two laser beams allow achieving maximum heat transfer and evaporation rate. Homogeneous heating is significantly inferior to local non-stationary heating in terms of all key criteria. The simple expressions serve to optimize the total efficiency coefficient.

Reasonable Time Requirement: ECtHR Approach

The concept of access to justice is enshrined in Article 6 of the European Convention on Human Rights. It encompasses a number of core rights and the requirements arising therefrom constitute the main obligations for high contracting parties to the convention. Thus, ensuring the materialization of those rights in their respective domestic legal systems should, in fact, be perceived as the sole priority of the member states in terms of guaranteeing adequate human rights protection framework. The right to a fair trial protected by Article 6 of the convention provides that everyone is entitled to a fair and public hearing within a reasonable time in the determination of his civil rights and obligations and of any criminal charge against him. In simpler words, it says that proceedings shouldn’t be excessively long. At first glance, the implementation of a reasonable time requirement seems very easy. On the other hand, if we look just a little bit deeper, several factors that hinder hearing from being within a reasonable timeframe will therefore appear, which as usual results in preventing the proper administration of the justice. Apparently, the importance of this right is itself obvious; however, alleging the violation to have proceedings concluded within a reasonable period of the time is by far the most common issue raised in applications to the ECtHR. The article analyzes the concept of the reasonable time requirement. Afterward,it describes the identification of the relevant period that ought to be taken into account while assessing the reasonableness. Lastly, the paper tries to illustrate the key criteria applied by ECtHR in order to determine the reasonableness of the proceedings referring key standards set by the court itself and examines if the methodology used by the court while assessing the reasonable length of the proceedings is the right approach to the problem.

Covalent-103: A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study of Bmf-500, an Oral Covalent FLT3 Inhibitor, in Adults with Acute Leukemia (AL)

Background: FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival. BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations. The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experiences either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML. Key inclusion criteria include ECOG PS ≤ 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/ PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS). The study was initiated in July 2023 and will enroll ~110 participants at approximately 30 sites.

Trial-in-Progress: A Phase 1/2 Multi-Center Study of Onct-808, a ROR1-Specific CAR T, in Adult Patients with Relapsed/Refractory Aggressive B Cell Lymphoma

BACKGROUND: The therapeutic landscape for B-cell lymphomas (BCL) leverages several modalities, including chemotherapy, targeted agents, adoptive cell therapy, and immunotherapy. While these approaches have shown clinical benefit, challenges remain, such as variable response rates, treatment resistance, and toxicities. ROR1-specific CAR T-cell therapy represents a promising potential advancement in the treatment of aggressive BCL in patients (pts) who have failed previous CD19 CAR T therapy. ROR1-targeted CAR T therapy offers several advantages that could address these challenges. By directing CAR T cells to specifically recognize and eliminate ROR1-expressing tumor cells, it offers a highly targeted approach with the potential for enhanced efficacy. Moreover, ROR1 is often highly expressed on aggressive BCL, making it a suitable therapeutic target. This focused approach may help overcome the limitations associated with current treatments and improve response rates. After birth ROR1 is predominantly expressed on malignant cells; therefore, this selective expression pattern may reduce the risk of toxicities, including off-tumor target elimination and non-specific activation of immune cells. The development of ROR1-specific CAR T holds promise in enhancing the treatment outcomes for patients with aggressive BCL. With targeted action and potential to reduce toxicity, ROR1-specific CAR T cell therapy offers an innovative and novel strategy for improving patient outcomes in BCL. The ROR1 binding moiety for ONCT-808 is derived from zilovertamab. Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022). METHODS: This is a Phase 1/2, single-arm, open-label, multi-center trial to evaluate the safety and efficacy of ONCT-808 in pts with aggressive BCL, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL) with no approved therapy available. The study comprises two distinct phases: Phase 1 for dose escalation followed by Phase 2 for dose expansion. In Phase 1, a standard 3+3 dose escalation design will be used with 3 provisional dose levels and expected sample size of up to 18 patients. Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion. The dose of ONCT-808 will be sequentially escalated to determine the recommended Phase 2 dose (RP2D) for LBCL and MCL cohorts. Bridging therapy is permitted if clinically indicated. Phase 2 will enroll LBCL and MCL patients into separate dose expansion cohorts at the RP2D determined in Phase 1. ONCT-808 will be administered as a single IV infusion of autologous CAR T cells. The primary outcomes include assessing the incidence, severity, and relationship of Dose Limiting Toxicities (DLT), Treatment Emergent Adverse Events (TEAE), and RP2D selection of ONCT-808. Secondary outcomes include evaluating the Overall Response Rate (ORR), Complete Response (CR) rate, Duration of Response (DOR), pharmacokinetics of ONCT-808, expansion, persistence of ROR1 CAR-positive T cells, overall safety and tolerability. Key inclusion criteria include histologically confirmed aggressive B-cell NHL, measurable lesions per Lugano criteria (Cheson, 2014), and relapsed/refractory (R/R) disease without available therapy (must be previously treated with systemic therapy, progressed after or ineligible for autologous HSCT, and received prior approved anti-CD19 CAR-T at least 6 months prior to enrollment unless refused/ineligible). Key exclusion criteria include previous ROR1-targeted therapy, ongoing immunosuppression, and CNS involvement. The trial is currently active and patients have been treated in the phase 1 dose escalation. Clinical Trial Identifier: NCT05588440

A Phase 1, Open-Label, Dose Escalation and Dose Expansion Study of CLN-978 (CD19XCD3XHSA) in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Background: Patients with B-cell non-Hodgkin lymphoma (B-NHL) who are refractory to/or have relapsed (R/R) after treatment with anti-CD20 monoclonal antibodies, either alone or in combination with standard-of-care chemotherapy, have a poor prognosis. Response rates tend to decrease and duration of response shortens with each successive line. CD19 represents a significant target for the development of novel immunotherapies for the treatment of patients with R/R B-NHL, many of whom develop disease that is refractory to CD20-containing regimens. CD19-directed therapies approved for B-NHL include an Fc-enhanced anti-CD19 monoclonal antibody, a CD19-directed antibody-drug conjugate, and several CD19-directed CAR-T cell products. While CAR-T approaches are an important alternative for some B-NHL subtypes, many patients still relapse, and challenges remain with toxicity and accessibility in the community setting. Consequently, substantial unmet needs remain for effective treatments with broad applicability across B-NHL subtypes and practice settings. CLN-978 is a fully human, half-life extended, single-chain T cell engaging construct targeting CD19 and CD3, with a human serum albumin (HSA) binding moiety for half-life extension. Preclinically, CLN-978 effectively redirects T cells to kill CD19-expressing malignant cells and has demonstrated potent in vitro and in vivo efficacy against cancer cells expressing very low levels of human CD19. Study Design and Methods: This is a phase 1, open-label, multi-center, first-in-human, dose escalation, and dose expansion study of CLN-978 in patients with R/R B-NHL. Adult patients (≥ 18 years of age) with one of the following CD19+ B-cell histologies: diffuse large B-cell lymphoma - de novo or transformed, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, or marginal zone lymphoma (nodal, extranodal, or mucosa-associated) for whom there is no available approved standard therapy will be recruited. Other key eligibility criteria include: ≥ 2 lines of prior chemotherapy, Eastern Cooperative Oncology Group Performance Status 0-2. Key exclusion criteria include prior treatment with allogeneic hematopoietic stem cell transplantation or any other investigational CD19 x CD3 T cell engager. Prior CAR-T therapy, unconjugated or radio-conjugated CD19 mAb, and CD19 antibody-drug conjugate are allowed. The study consists of 2 parts: 1) a dose escalation phase commencing with accelerated titration in single-patient cohorts followed by a conventional 3+3 dose escalation design to identify the recommended phase 2 dose (RP2D) and 2) a dose expansion phase to further characterize the safety and preliminary efficacy of CLN-978 in disease-specific cohorts at the RP2D. CLN-978 will be subcutaneously (SC)-administered once weekly (QW) in 28-day cycles until progressive disease, intolerable toxicity, or a maximum of 24 cycles of treatment. Initial administration of CLN-978, inclusive of potential priming doses and the first target dose, will be administered on an inpatient basis. Subsequent doses may be given in the outpatient setting. Based on emerging data, less frequent administration schedules may be implemented in Cycle 4 and beyond as approved by the Safety Review Committee. Safety, pharmacokinetic (PK), pharmacodynamic, and preliminary efficacy assessments will guide the selection of the dose and schedule for further evaluation. The primary endpoint is safety. Key secondary endpoints include PK, anti-drug antibodies, overall response rate, duration of response, time to response, time to subsequent anti-lymphoma therapy, progression-free survival, and overall survival. Approximately 90 patients (30 in dose escalation and 60 in dose expansion) will be enrolled at approximately 6 sites in the U.S., reflecting both community and academic centers. The study is currently enrolling (NCT05879744).

First-in-Human Dose-Escalation and -Expansion Trial with Sirpα Antibody BYON4228 in R/R B-Cell NHL

Introduction: Blocking of the immune checkpoint CD47-SIRPα promotes myeloid cell-mediated innate as well as adaptive immunity towards tumor cells. Antibodies in development are either directed against CD47 or SIRPα and in combination with tumor-targeting antibodies, checkpoint inhibitors, chemotherapeutics or other agents. The humanized SIRPα antibody BYON4228 (van Helden et al (2023) JITC 11: e006567) has been designed with three distinguishing characteristics compared to other CD47- or SIRPα-directed therapies which makes BYON4228 potentially best-in-class: 1.High specificity for SIRPα and no binding to SIRPγ on T cells which enables maximal contribution of T cells and therefore maximal anti-tumor immune response; 2.Silenced Fc backbone (IgG1-L234A/L235) which potentially results in reduced toxicity as confirmed in nonclinical studies showing no anemia or neutropenia in monkey; 3.Binding to both allelic forms of SIRPα (α 1 and α BIT) covering a broad patient population. Phase 1 clinical trial design: BYON4228.001 (NCT05737628) is the first-in-human clinical trial of BYON4228, in combination with rituximab, in relapsed or refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL). Part 1 (dose escalation) evaluates the safety, tolerability and Pharmacokinetics (PK) of, and receptor occupancy by BYON4228 to determine the maximum tolerated dose (MTD) or optimal biological dose (OBD) if the MTD is not reached, and recommended dose for expansion (RDE). A 28-day flat dose escalation schedule starting at 7 mg will be followed in a standard 3+3 design. Notably, only 1 cycle BYON4228 monotherapy will be given in each patient before combining with rituximab (375 mg/m 2 first cycle weekly administration; thereafter every 4 weeks for a total of 6 cycles). In part 2 (cohort expansion) BYON4228 + rituximab combination therapy will be given from cycle 1 onwards to further evaluate safety and efficacy in up to 24 additional diffuse large B cell lymphoma (DLBCL) patients and up to 24 patients with either marginal zone lymphoma (MZL) or follicular lymphoma (FL). This trial design of only 1 cycle monotherapy and swiftly moving into combination therapy not only allows to investigate PK and safety of BYON4228 but also efficacy of combination treatment with rituximab in a relevant therapeutic setting. Enrollment is ongoing in The Netherlands, United Kingdom, Italy and Spain since June 2023. Key inclusion criteria include, for part 1: B-cell NHL expressing CD20 by immunohistochemistry (IHC) or flow cytometry, R/R to at least 2 prior lines of therapy; for part 2, cohort A: Histologically confirmed DLBCL expressing CD20 R/R to front-line therapy, or second-line salvage regimens; for part 2, cohort B: Histologically confirmed MZL or FL (Grade 1-3a) expressing CD20, R/R to at least 2 prior lines of therapy. Autologous or allogeneic hematopoietic cell transplantation and autologous CAR-T cell therapy are allowed as prior lines. Key exclusion criteria include prior treatment with CD47- or SIRPα- targeting agents at any time; other anticancer therapy including investigational agents within 2 weeks or within at least 4 times the elimination half-life; Burkitt's lymphoma; history of active auto-immune disorders, active infections or uncontrolled systemic disease. Tumor response is determined according to Lugano and LYRIC criteria. An extensive biomarker program in the peripheral blood and bone marrow is included in the trial.

FORTITUDE: A Phase 2 Open-Label Study in Progress to Evaluate Etavopivat for the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes

Background: Most patients with lower-risk myelodysplastic syndrome (LR-MDS) develop anemia and a high proportion of patients become dependent on red blood cell (RBC) transfusions. MDS-related anemia is associated with low hemoglobin (Hb) levels, iron overload and poor quality of life. Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population. Etavopivat is an investigational, once-daily, selective erythrocyte pyruvate kinase (PKR) activator in development for the treatment of sickle cell disease (SCD) and anemia in patients with LR-MDS. In a phase 1 study in adult and adolescent patients with SCD by Saraf et al. HemaSphere. (2022), etavopivat 400 mg once daily was considered well tolerated and showed sustained Hb increases up to 12 weeks for most patients. Additional studies in healthy volunteers and patients with SCD support an acceptable safety profile together with improved RBC health and function during continuous treatment with etavopivat. In patients with LR-MDS, ineffective hematopoiesis may be due, in part, to insufficient ATP production, leading to increased erythroid lineage apoptosis. By activating PKR, etavopivat may improve RBC health and function by stimulating energy production (increasing ATP levels), increasing Hb levels (decreasing anemia), and decreasing erythroid lineage apoptosis. Aims:Describe the design of a multicenter, open-label, phase 2 study (FORTITUDE; NCT05568225) evaluating hematologic improvements in patients with very low-, low- and intermediate-risk MDS during treatment with etavopivat. Study design:Key eligibility criteria include age ≥18 years; very low-, low- and intermediate-risk MDS per the Revised International Prognostic Scoring System; and anemia defined by mean Hb <10.0 g/dL and <3 RBC transfusions <16 weeks prior to first dose for non-transfusion-dependent (NTD) patients or ≥3 units of RBCs for anemia <16 weeks prior to first dose for transfusion-dependent (TD) patients. Key exclusion criteria include MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality, history of acute myeloid leukemia, and an absolute neutrophil count <0.5 × 10 9/L. Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients. Patients will receive etavopivat 400 mg once daily for at least 48 weeks. Treatment may be continued beyond 48 weeks in patients demonstrating clinical benefit. The primary objective of the study is to assess hematologic improvements based on an erythroid response over any continuous period ≥8 weeks within 24 weeks on etavopivat treatment in patients with LR-MDS. The primary endpoint will be based on the combined incidence of: ≥1.5 g/dL increase in Hb from baseline maintained for ≥8 consecutive weeks for NTD patients; absence of any transfusion for ≥8 consecutive weeks for low transfusion-burden patients; and reduction by ≥50% of RBC units for ≥8 consecutive weeks for high transfusion-burden patients. Safety, tolerability, pharmacokinetic, and pharmacodynamic properties of etavopivat will be evaluated. FORTITUDE is open for enrollment in Canada, France, Germany, and the USA. Planned enrollment includes approximately 15 patients in each of the three transfusion requirement-based groups (Figure). Statistical analysis: The primary endpoint (pooled incidence) will be tested with a one-sided Fisher's exact test at the significance level of 0.025 where 0.2 is the assumed null proportion. Summary:Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia.

Phase I Safety and Preliminary Efficacy of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), even when treated with novel targeted agents, generally have only limited benefit (Rule et al., Leukemia 2018). The triple combination of the first-generation Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, the BCL-2 inhibitor, venetoclax, and anti-CD20 monoclonal antibody, obinutuzumab has demonstrated preliminary safety and efficacy in R/R and treatment naïve (TN) MCL (Le Gouill et al., Blood 2021). We therefore hypothesized that given the favorable toxicity profile of the second-generation BTKi, acalabrutinib, when given in combination with venetoclax and obinutuzumab (AVO), would be effective and well tolerated in both R/R and TN MCL. Here, we report the results of the phase I dose-finding cohort of AVO in patients with R/R MCL. Methods: This is an investigator-initiated, multicenter, multi-cohort phase I/II trial (NCT04855695). The primary endpoints of the phase I portion are the recommended phase II dose (RP2D) and the safety and tolerability of AVO in R/R MCL. The study was designed to evaluate up to 2 dose levels of acalabrutinib, starting with the FDA-approved dose (100 mg po bid, dose level 0 [DL0]) followed by a lower dose (100 mg po daily, DL-1) if dose limiting toxicities (DLTs) occurred in > 1/6 patients in DL0 during the first 4 cycles. Patients were treated in 28-day cycles with acalabrutinib starting with cycle 1, followed by obinutuzumab in cycle 2 (100 mg IV on day 1, 900 mg IV on day 2, 1000 mg IV on days 8 and 15, and on day 1 of cycles 3-7), and venetoclax (weekly dose ramp-up starting in cycle 3 to a target dose of 400 mg daily). Acalabrutinib and venetoclax were continued indefinitely and obinutuzumab maintenance was given every 2 cycles starting with cycle 9 for 12 doses. Patients with progressive disease (PD) or who were unable to receive > 80% of the doses of acalabrutinib and venetoclax during the first 4 cycles were replaced. Key eligibility criteria included R/R MCL after at least one anti-CD20 mAb-based therapy, ECOG PS ≤ 2, and adequate hematologic and organ function. Key exclusion criteria were progression or relapse following prior BTKi or BCL-2 inhibitor and CNS involvement. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy, respectively. Results: As of July 26, 2023, 9 patients in DL0 were evaluable for response as 3 patients were replaced prior to reaching the DLT window. The median age was 67 (range 63-79). 78% were male. Median number of prior treatments was 1 (range 1-2). 33% relapsed after autologous stem cell transplant and 22% had primary refractory disease. All patients had advanced stage MCL, with stage IV disease in 89%. MIPI score was 22% high, 56% intermediate, and 22% low risk. Ki67 index ≥ 30% in 44% and ≥ 50% in 33%. 33% patients had complex karyotype, 22% TP53 mutation, 33% p53 IHC expression > 50%, and 33% blastoid variant. No DLTs were observed and DL0 was determined to be the RP2D. All 9 patients were evaluable for toxicity (Figure 1A). Hematologic toxicity included neutropenia (67%; 33% Gr 3), thrombocytopenia (56%; 22% Gr 3/4), and anemia (22%; all Gr 3). The most common toxicities were headache (77%; all Gr 1/2), bruising (67%; all Gr 1), diarrhea (44%; all Gr 1/2), and upper respiratory infection (22%; 11% Gr 3). There were no serious adverse events. There was no occurrence of febrile neutropenia, atrial fibrillation, bleeding, or laboratory or clinical tumor lysis syndrome. Median follow-up was 6 months (range 1-21). ORR was 78% (7/9) and CR rate was 67% (6/9) after 3 cycles of AVO. Both patients with TP53 mutation and 2/3 patients with blastoid variant achieved CR. Of the 3 patients replaced prior to the DLT window, 2 patients had PD and 1 patient was unable to receive > 80% of the acalabrutinib and venetoclax doses due to grade 4 thrombocytopenia, although achieved CR. 5 patients (56%) remain on treatment and in CR. 1 patient achieved PR after cycle 3 but progressed after cycle 7. Median overall and progression-free survival were not reached. Conclusions: AVO is safe and feasible in patients with R/R MCL with no DLTs observed. RP2D was determined at the full FDA approved dosage of all three drugs. Preliminary efficacy is encouraging in this high-risk R/R MCL population. The phase II TN transplant ineligible or TP53 mutated MCL cohort is now enrolling with minimal residual disease (MRD)-guided time-limited therapy (Figure 1B). The phase I R/R expansion cohort will also open to enrollment.