Monitoring Committee Research Articles

Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.

B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes. We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or high risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival. The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a high relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone. Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or high risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).

Post-Pandemic Analysis of Governance and Performance in Indonesia’s Regional Development Banks

This study examines the governance structures and mechanisms influencing the performance of Indonesia’s regional development banks (BPDs) during and beyond the COVID-19 pandemic. By analyzing financial and annual reports from 27 regional development banks across Indonesia, the study explores both the immediate and lasting impacts of governance elements, including board size, board independence, and committee structures, on bank performance. Using a two-stage least squares (2SLS) regression model, findings reveal that certain governance elements, such as the risk monitoring committee size, positively impacted performance during the pandemic, whereas larger board sizes and higher board independence were associated with negative outcomes. Additionally, other governance factors, such as board meeting frequency and audit committee size, did not significantly influence performance during the crisis. The research highlights that the stability observed in BPDs during the pandemic was primarily driven by external factors, including regional economic growth and credit expansion, rather than governance mechanisms alone. These findings suggest that while crisis-era governance structures were adequate during the pandemic, post-pandemic recovery and resilience will require more adaptable governance frameworks. As BPDs face evolving challenges in the financial sector, this study underscores the importance of enhancing strategic oversight and adjusting governance practices to foster long-term stability. This research contributes to the literature on governance and crisis management in regional banks, offering insights for regulators and practitioners seeking to reinforce governance frameworks that support sustainable performance in the face of new economic realities.

Insights into Health Program Implementation and Evaluation in Iran: A Brief Review of National Healthcare Programs in Iran.

Healthcare program monitoring can play a key role in evaluating their implementation and identifying their strengths and weaknesses. This study was performed with the exploratory sequential mixed methods design in 2023 at Tehran, Iran. The information was categorized into indicators, refining, analysis, interpretation, reporting, and proposed challenges and recommendations. Medical Sciences Department of Public Health (TUMSDoPH) evaluation of its public health programs revealed a comprehensive approach covering a wide spectrum from disease management to health promotion, emphasizing electronic health records, targeted disease interventions, and strategies for non-communicable diseases, alongside efforts to enhance community health. There is a need for initiating "the monitoring committee" under the supervision of the deputy chancellor for public health to monitor key performance indicators and policies to discover the problems of each part of the health system and provide recommendations.

Pragmatic monitoring of emerging efficacy data in randomized controlled trials.

Monitoring the conduct of phase III randomized controlled trials is driven by ethical reasons to protect the study integrity and the safety of trial participants. We propose a group sequential, pragmatic approach for monitoring the accumulating efficacy information in randomized controlled trials. The "Population Health Research Institute boundary" is simple to implement and sensible, as it considers the reduction in uncertainty with increasing information as the study progresses. It is also pragmatic, since it takes into consideration the typical monitoring behavior of monitoring committees of large multicenter trials and is relatively easily implemented. It not only controls the overall Lan-DeMets type I error probability (alpha) spent, but performs better than other group sequential boundaries for the total nominal study alpha. We illustrate the use of our monitoring approach in the early termination of two past completed trials.

The multilevel determinants of overlapping membership on board committees: Evidence from Chinese banks

This study manually collects data on 4090 board committee members from 36 listed banks in 11 regions of China from 2007 to 2020, uses a hierarchical linear model, and integrates institutional and resource dependence theories to examine the multilevel determinants of overlapping membership on board committees. The results show that low legalization and the absence of chief risk officers promote overlapping membership on board committees. Directors who have financial expertise, are shorter-tenured, and do not have social relationships with senior leaders sit on more board committees. Further analysis shows that information and resource needs are more likely to drive overlapping membership on board monitoring committees, and independent directors with lower information acquisition costs sit on more board committees. The moderating analysis between multilevel factors shows that legalization and the presence of chief risk officers substitute for, while religion and board interlocks complement director-level information and resource needs.

Descemet Endothelial Thickness Comparison Trial II (DETECT II): multicentre, outcome assessor-masked, placebo-controlled trial comparing Descemet membrane endothelial keratoplasty (DMEK) to Descemet stripping only (DSO) with adjunctive ripasudil for Fuchs dystrophy

IntroductionIt remains uncertain whether Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping only (DSO) yields better outcomes in patients with symptomatic Fuchs endothelial corneal dystrophy (FECD). This paper presents the...

Stakeholders' Perspectives on Current Issues in Data Monitoring Committees

ABSTRACTData Monitoring Committees (DMCs) are groups of experts that review accumulating data from one or more ongoing clinical studies and advise the Sponsor regarding the continuing safety of study subjects along with the continuing validity and scientific merit of the study. Although DMCs are widely used, considerable variability exists in their conduct. This paper offers recommendations, derived from sessions given at the 2023 Central European Network International Biometric and Statisticians in the Pharmaceutical Industry Conferences' and the authors' experiences. We focus on four topics that are part of the DMC process and where there is unclarity and inconsistency in current practices: (1) Communication with the DMC—We reflect on the importance of effective, proper communication channels between the DMC and relevant stakeholders to foster collaboration and exchange of critical information while retaining study integrity throughout. (2) Open sessions—We discuss the benefits of incorporating open sessions in DMC meetings to enhance transparency, inclusivity, and the consideration of diverse perspectives, as well as pitfalls of open sessions. (3) Access to efficacy data—We highlight the need for appropriate access to efficacy data by DMCs and discuss how to implement this in practice and how to address potential concerns regarding multiplicity. (4) Interactive data displays—We outline the utilization of interactive data displays to facilitate a more intuitive understanding of study results by the DMC. By addressing these topics, we aim to provide comprehensive practical recommendations that bridge the gap between current practices and optimal DMC functionality.

The Effect of Gender Diversity and Expertise of Risk Monitoring Committee on Equity Investment Risk in Islamic Banks

The study of risk in Islamic banks emphasizes more on the general risk of Islamic banks, this general risk in Islamic banks arises from transactions unrelated to special transactions of Islamic banks. The profit and loss sharing system implemented by Islamic banks raises equity investment risk (EIR). This study uses the agency theory approach in explaining EIR. In the agency theory approach, the risk monitoring committee has the responsibility of evaluating and monitoring the risk management in Islamic banks. The characteristics of risk monitoring committee members can affect the capability of the risk monitoring committee to provide risk management assessments and policies and can affect the effectiveness of the risk monitoring committee in carrying out its duties and responsibilities. The study population was 109 Islamic banks spread across 18 countries in ASEAN and the Gulf Cooperation Council, where the sample was observed in 2021 during the peak of COVID-19. The results of this study indicate that the gender diversity of the risk management committee and the risk management monitoring committee’s expertise in accounting/risk management have a significant negative effect on equity investment risk.

Protocol amendment for ENSEMBLE study: A multicenter, randomized, phase III trial to test the superiority of consolidation irinotecan, capecitabine and oxaliplatin vs capecitabine and oxaliplatin following short course radiotherapy as total neoadjuvant therapy in patients with locally advanced rectal cancer—Changing the irinotecan dosage.

TPS99 Background: Total neoadjuvant therapy (TNT) presents a promising approach for treating patients (pts) with locally advanced rectal cancer (LARC). TNT not only enhances outcomes for LARC pts but also contributes to improving their quality of life by offering non-operative management (NOM) for patients with complete clinical response (cCR) or near-complete clinical response (nCR). We are currently conducting a phase III trial, the ENSEMBLE study, which was presented at ASCO Breakthrough 2023. At this stage, we have modified the protocol for this study. Additionally, we are conducting translational research (TR) to establish clear criteria for NOM following TNT. Methods: In the ENSEMBLE study, the experimental treatment group received short-course radiotherapy (SCRT) (5×5 Gy) followed by six cycles of CAPOXIRI (capecitabine 800 mg/m2 [orally, twice daily, days 1-14], oxaliplatin 130 mg/m2 [intravenously, day 1], and irinotecan 200 mg/m2 [intravenously, day 1, every 3 weeks]). The standard-of-care group received SCRT (5×5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 [orally, twice daily, days 1-14], oxaliplatin 130 mg/m2 [intravenously, day 1, every 3 weeks]). However, the experimental treatment group experienced a higher rate of adverse events due to the high starting dose of irinotecan. After consulting the data and safety monitoring committee (DSMC), it was recommended to reduce the starting dose of irinotecan. Results: Enrollment for the ENSEMBLE study commenced in November 2022. By August 2023, severe adverse events necessitating emergency reporting had occurred in the experimental treatment group. In response to these adverse events, the DSMC was consulted, leading to the reduction of the starting dose of irinotecan to 150 mg/m2. Following this adjustment, no severe adverse events requiring emergency reporting were observed during the experimental treatment with CAPOXIRI. We are currently continuing the ENSEMBLE study to advance treatment options for LARC pts. The TR component of the ENSEMBLE study involves genomic profiling through whole genome plus RNA sequencing of tissue and blood samples, as well as circulating nucleic acid sequencing (cNAS). Additionally, all imaging data (MRI, CT, and colonoscopy) and clinical information are being collected to develop criteria for NOM. Conclusions: A starting dose of irinotecan at 150 mg/m2 appears to be feasible after SCRT in the ENSEMBLE study. Furthermore, the ENSEMBLE study aims to establish clear NOM criteria through deep learning with TR. Clinical trial information: NCT05646511 / jRCTs031220342 .

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults

BackgroundMany older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)–negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.MethodsIn a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point.ResultsThe data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P=0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group.ConclusionsThe addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.)

Protect peripheral intravenous catheters: a study protocol for a randomised controlled trial of a novel antimicrobial dressing for peripheral intravenous catheters (ProP trial)

IntroductionPeripheral intravenous catheters (PIVCs) are the most commonly used vascular access device in hospitalised patients. Yet PIVCs may be complicated by local or systemic infections leading to increased healthcare costs....

Inhaled treprostinil in pulmonary hypertension associated with COPD: PERFECT study results.

Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study (ClinicalTrials.gov: NCT03496623) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. The risk-benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.

Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer

Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome. A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. ClinicalTrials.gov Identifier: NCT02927249.

Schema therapy versus treatment as usual for outpatients with difficult-to-treat depression: study protocol for a parallel group randomized clinical trial (DEPRE-ST)

BackgroundAbout one third of patients with depression are in a condition that can be termed as “difficult-to-treat”. Some evidence suggests that difficult-to-treat depression is associated with a higher frequency of childhood trauma and comorbid personality disorders or accentuated features. However, the condition is understudied, and the effects of psychotherapy for difficult-to-treat depression are currently uncertain. The aim of this trial is to investigate the beneficial and harmful effects of 30 sessions of individual schema therapy versus treatment as usual for difficult-to-treat depression in the Danish secondary, public mental health sector.MethodsIn this randomized, multi-centre, parallel-group, superiority clinical trial, 129 outpatients with difficult-to-treat depression will be randomized (1:1) to 30 sessions of individual schema therapy or treatment as usual; in this context mainly group-based, short-term cognitive behaviour or psychodynamic therapy. The primary outcome is the change from baseline in depressive symptoms 12 months after randomization, measured on the observer-rated 6-item Hamilton Rating Scale for Depression. The secondary outcomes are health-related quality of life assessed with the European Quality of Life 5 Dimensions 5 Level Version, functional impairment assessed with the Work and Social Adjustment Scale, psychological wellbeing assessed with the WHO-5 Well-being Index, and negative effects of treatment assessed with the Negative Effects Questionnaire. Exploratory outcomes are improvement on patient self-defined outcomes, personal recovery, anxiety symptoms, anger reactions, metacognitive beliefs about anger, and perseverative negative thinking. Outcomes will be assessed at 6, 12, and 24 months after randomization; the 12-month time-point being the primary time-point of interest. Outcome assessors performing the depression-rating, data managers, statisticians, the data safety and monitoring committee, and conclusion makers for the outcome article will be blinded to treatment allocation and results. To assess cost-effectiveness of the intervention, a health economic analysis will be performed.DiscussionThis trial will provide evidence on the beneficial and harmful effects, as well as the cost-effectiveness of schema therapy versus treatment as usual for outpatients with difficult-to-treat depression. The results can potentially improve treatment for a large and understudied patient group.Trial registrationClinicalTrials.gov NCT05833087. Registered on 15th April 2023 (approved without prompts for revision on 27th April 2023).

Do board monitoring and audit committee quality help risky firms reduce CSR controversies?

Do board monitoring and audit committee quality help risky firms reduce CSR controversies?

International guidelines for intratumoral and intranodal injection of NBTXR3 nanoparticles in head and neck cancers.

An international multidisciplinary panel of experts aimed to provide consensus guidelines describing the optimal intratumoral and intranodal injection of NBTXR3 hafnium oxide nanoparticles in head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, and cervical lymph nodes and to review data concerning safety, feasibility, and procedural aspects of administration. The Delphi method was used to determine consensus. A 4-member steering committee and a 10-member monitoring committee wrote and revised the guidelines, divided into eight sections. An independent 3-member reading committee reviewed the recommendations. After two rounds of voting, strong consensus was obtained on all recommendations. Intratumoral and intranodal injection was deemed feasible. NBTXR3 volume calculation, choice of patients, preparation and injection procedure, potential side effects, post injection, and post treatment follow-up were described in detail. Best practices for the injection of NBTXR3 were defined, thus enabling international standardization of intratumoral nanoparticle injection.

Abstract CT274: BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC)

Abstract Background: ESCC is the predominant histological subtype of esophageal cancer, accounting for 85% of cases. Patients (pts) with locally advanced/metastatic ESCC have poor clinical outcomes, with a 5-year survival rate of 6.1% for pts with distant metastases. 1L treatment with programmed cell death protein-1 (PD-1) inhibitors + platinum-based chemo has become the new standard of care for metastatic ESCC, however, there is an unmet need for enhanced treatment efficacy and a prolonged life span. LBL-007 is a monoclonal antibody (mAb) against lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that negatively regulates T-cell activity. TIS is an anti-PD-1 mAb that blocks the PD-1/programmed death-ligand 1 (PD-L1) immune checkpoint, resulting in T-cell activation. This study (NCT06010303) aims to evaluate the efficacy and safety of LBL-007 + TIS + chemo as a 1L treatment in pts with unresectable, locally advanced/metastatic ESCC. Methods: This phase 2 study will enroll approximately 116 pts with a pathologically confirmed diagnosis of unresectable, locally advanced/metastatic ESCC and no prior systemic therapy. Pts will be randomized 2:1 to either Arm A (LBL-007 600 mg intravenously [IV] every 3 weeks [Q3W] + TIS 200 mg IV Q3W + chemo doublet) or Arm B (TIS 200 mg IV Q3W + chemo doublet), stratified by PD-L1 expression (tumor area positivity score ≥10% or &amp;lt;10%). The chemo doublet will consist of either cisplatin (60-80 mg/m2 IV Q3W) + 5-fluorouracil (750-800 mg/m2 IV daily on Days 1-5 Q3W), or cisplatin + paclitaxel (175 mg/m2 IV Q3W), determined by the investigator before randomization. Treatments will be administered until disease progression, intolerable toxicity, or withdrawal for other reasons. The primary endpoint is the overall response rate, as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints include progression-free survival, duration of response, and disease control rate (all by investigator per RECIST v1.1), and the incidence and severity of adverse events per National Cancer Institute-Common Terminology Criteria for Adverse Events v5.0. A safety monitoring committee is monitoring the safety of LBL-007 + TIS + chemo vs TIS + chemo. Exploratory endpoints include comparison of overall survival, assessment of predictive, prognostic, and pharmacodynamic biomarkers, pharmacokinetic evaluation of LBL-007 and TIS, and immunogenicity. The study is currently recruiting at approximately 46 sites across Asia, including Taiwan, mainland China, South Korea, and Thailand. Citation Format: Sook Ryun Park, Ming-Huang Chen, Arunee Dechaphunkul, Ningning Ding, Xiao Lin, Jinghui Zhang, Vivian Li, Qiao Li, Yi Ba. BGB-A317-LBL-007-202: A phase 2, randomized, active-controlled, open-label study to evaluate the efficacy and safety of LBL-007 (anti-LAG-3) in combination with tislelizumab (TIS; anti-PD-1) plus chemotherapy (chemo) as first-line (1L) treatment in patients with unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT274.

Abstract CT165: A phase 1/2a, multicenter, open-label, first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1311 (a B7-H3-targeting ADC) in patients with advanced/metastatic solid tumors

Abstract Background: B7 homolog 3 protein (B7-H3, an immune checkpoint molecule) overexpression correlates with disease progression and poor prognosis in various cancers, including lung cancer, esophageal cancer, prostate cancer, and melanoma, is therefore as an ideal candidate for targeted immunotherapy. DB-1311 is an antibody-drug conjugate (ADC) comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor via a maleimide tetrapeptide-based cleavable linker, with a drug-to-antibody ratio of approximately 6. Preclinical studies of DB-1311 demonstrated promising antitumor activity in solid tumors and a tolerable safety profile, warranting further clinical development. Methods: This global, first-in-human, Phase 1/2a study includes dose escalation and expansion parts to assess the safety, tolerability, pharmacokinetics, and antitumor activity of DB-1311 in patients (pts) with pretreated advanced/metastatic solid tumors (NCT05914116). Eligible pts must have tumor that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment, or for which no standard treatment is available; have ECOG PS ≤1; and evidence adequate organ function. Up to 5 ascending dose levels of DB-1311 will be evaluated with an accelerated titration at first dose followed by a classic “3+3” design to identify the maximum tolerated dose and/or recommended phase 2 dose in pts with solid tumors. Phase 2a part will initiate with a randomization (1:1) cohort for dose optimization in pts with small cell lung cancer with two dose levels identified by the safety monitoring committee based on cumulative data from Phase 1 part. The other five cohorts will enroll pts with non-small cell lung cancer, esophageal squamous cell carcinoma, castration-resistant prostate cancer, melanoma, and other solid tumors at the dose level(s) determined based on cumulative data. DB-1311 will be administrated intravenously as monotherapy until disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. The study plans to enroll approximately 90 pts in Phase 1 and 190 in Phase 2a from locations including but not limited to Australia, United States, China, and Taiwan. To the data cut-off 05 Dec 2023, 11 pts have been enrolled in the study. Citation Format: Ying Cheng, Aaron Lisberg, Charlotte Lemech, Afaf Abed, Arvind Chaudhry, Andrew Schmidt, Xin Lu, Zhongyuan Zhu, Wei Gu, Yang Qiu, Rong Shi, Bin Zhang. A phase 1/2a, multicenter, open-label, first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1311 (a B7-H3-targeting ADC) in patients with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT165.

First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors.

Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of tuvusertib monotherapy. Ascending tuvusertib doses were evaluated in 55 patients with metastatic or locally advanced unresectable solid tumors. A safety monitoring committee determined dose escalation based on PK, PD, and safety data guided by a Bayesian 2-parameter logistic regression model. Molecular responses (MR) were assessed in circulating tumor DNA samples. Most common grade ≥3 treatment-emergent adverse events were anemia (36%), neutropenia, and lymphopenia (both 7%). Eleven patients experienced dose-limiting toxicities, most commonly grade 2 (n = 2) or 3 (n = 8) anemia. No persistent effects on blood immune cell populations were observed. The RDE was 180 mg tuvusertib QD (once daily), 2 weeks on/1 week off treatment, which was better tolerated than the MTD (180 mg QD continuously). Tuvusertib median time to peak plasma concentration ranged from 0.5 to 3.5 hours and mean elimination half-life from 1.2 to 5.6 hours. Exposure-related PD analysis suggested maximum target engagement at ≥130 mg tuvusertib QD. Tuvusertib induced frequent MRs in the predicted efficacious dose range; MRs were enriched in patients with radiological disease stabilization, and complete MRs were detected for mutations in ARID1A, ATRX, and DAXX. One patient with platinum- and PARP inhibitor-resistant BRCA wild-type ovarian cancer achieved an unconfirmed RECIST v1.1 partial response. Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.

Social learning to promote forest restoration in a semi-arid landscape in North Africa

Forest restoration is a suitable tool to mitigate land degradation and enhance the supply of vital goods and services. Social participation in forest restoration has gained increasing interest. Yet, the impact of participation on people's perception of ecological restoration and the restoration process has barely been addressed despite its relevance for the long-term success of restoration actions. We assessed mutual learning of different stakeholder groups in a ten-year demonstration project, and its potential to foster continued participatory forest restoration in Beni Boufrah valley, a semiarid area located in North Morocco. We performed face-to-face interviews to assess post-restoration individual learning for a subset of 15 highly engaged stakeholders using five components of social learning: reciprocal determinism, self-reflective capability, expectations, self-regulation and locus of control. Furthermore, we organized a workshop to assess collective learning in the study area. The lessons learnt by the project team was described using monitoring vegetation measurements, field visits and meetings, and stakeholder recommendations. Two thirds of the stakeholders showed an increasing awareness of the reciprocal relationship between people and the environment, while recognizing the inappropriateness of current behaviors and practices. Farmers showed continuous mistrust towards the Forestry Agency which justifies the need for more innovative approaches to resolve persistent conflicts, integrate forest and agricultural interventions and establish new mechanisms for economic motivation. Stakeholders acquired theoretical and practical concepts on forest restoration, but self-initiated activities were scarce and reinforcement of environmental awareness is still needed. There was a high impact of drought on seedling survival and growth along with a decrease in stakeholder engagement over the years. We could identify and implement a series of practical corrective measures, namely participatory re-planting, plot fencing, establishment of a local monitoring committee, and raising awareness activities. Such participatory implementation of corrective measures may enhance the credibility of the restoration process and it can be further tested in similar semiarid areas of North Africa even at a larger scale.