Monitoring Committee Research Articles

Abstract P2-13-35: Pyrotinib combined with fulvestrant in women with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer: A single-arm phase II clinical trial

Abstract Background: HR+/HER2+ breast cancer is a unique molecular subtype of HER2+ breast cancer, which is characterized by mild biological behavior and is sensitive to endocrine therapy. Although the standard treatment for HR+/HER2+ metastatic breast cancer is chemotherapy combined with anti-HER2 therapy, this combination is not ideal for patients because of the heavy side effects of chemotherapy. Previous studies have shown that endocrine therapy combined with anti-HER2 therapy can also bring survival benefits to these patients. However, due to the limitations of previous treatment, the optimal combination mode of endocrine and anti-HER2 therapies has not been found. Pyrotinib is the most efficient pan-HER tyrosine kinase inhibitor (TKI) with irreversible blocking of HER2, while fulvestrant is the most potent estrogen receptor (ER) inhibitor. Previous cell experiments showed the cross-talk between ER and HER2 receptor pathways, indicating that the two signal pathways were important mechanisms of drug resistance for each other. Further research showed that ER inhibitor fulvestrant had synergistic effect with HER2 inhibitor pyrotinib. Therefore, we firstly explored the efficacy and safety of pyrotinib combined with fulvestrant in the treatment of HR+/HER2+ metastatic breast cancer.Methods: Eligible patients had histologically confirmed HR+/HER2+ metastatic breast cancer with no more than one line of prior treatment for metastatic disease. Those with central nervous system metastases or any prior HER2 TKI were excluded. Patients were treated with oral pyrotinib 400 mg once daily plus intramuscular injection of fulvestrant 500 mg on days 1, 15, and 29, and once every 28 days thereafter. The primary endpoint was progression-free survival (PFS), as assessed by the data and safety monitoring committee. Secondary endpoints included objective response rate, disease control rate (DCR), overall survival and safety. We also explored the efficacy of subgroups defined by different gene signatures, which were identified using comprehensive genomic variation profiling (FoundationOne CDx). This study is registered with ClinicalTrials.gov, NCT04034589.Results: From July 9, 2019 to June 20, 2021, 34 patients were enrolled; 19 (55.8%) patients had visceral metastases. Of 14 patients with measurable disease according to RECIST 1.1, seven (50%) achieved objective response. The DCR was 84.6%. Nine of the 34 included patients discontinued treatment because of disease progression, and PFS was immature. Twelve patients had available data of comprehensive genomic variation profiling, and the results showed that six patients had PIK3CA mutation, ten had TP53 mutation, and 11 had ErbB2 overexpression. The most common treatment-related adverse events were diarrhea and fatigue. The incidence of grade 3 or greater diarrhea was 12.1% (4/33) in patients with available safety data. No patient discontinued treatment because of adverse events. Conclusions: The combination of pyrotinib and fulvestrant was convenient and effective with manageable toxicity, which may offer a chemotherapy-free alternative treatment option for patients with HR+/HER2+ metastatic breast cancer. Citation Format: Ying Wang, Jianli Zhao, Zhongyu Yuan, Guorong Zou, Haiyan Li, Linxiaoxiao Ding, Yaping Yang, Jie Chai, Donggeng Liu, Herui Yao. Pyrotinib combined with fulvestrant in women with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer: A single-arm phase II clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-35.

Korean Medicine Clinical Practice Guidelines for Lumbar Herniated Intervertebral Disc in Adults: Based on Grading of Recommendations Assessment, Development and Evaluation (GRADE).

A significant number of individuals suffer from low back pain throughout their lifetime, and the medical costs related to low back pain and disc herniation are gradually increasing in Korea. Korean medicine interventions have been used for the treatment of lumbar intervertebral disc herniation. Therefore, we aimed to update the existing Korean medicine clinical practice guidelines for lumbar intervertebral disc herniation. A review of the existing guidelines for clinical treatment and analysis of questionnaires targeting Korean medicine doctors were performed. Subsequently, key questions on the treatment method of Korean medicine used for disc herniation in actual clinical trials were derived, and drafts of recommendations were formed after literature searches using the Grading of Recommendations, Assessment, Development and Evaluation. An expert consensus was reached on the draft through the Delphi method and final recommendations were made through review by the development project team and the monitoring committee. Fifteen recommendations for seven interventions for lumbar disc herniation were derived, along with the grade of recommendation and the level of evidence. The existing Korean medicine clinical practice guidelines for lumbar intervertebral disc herniation have been updated. Continuous updates will be needed through additional research in the future.

The Influence of the Number of Board of Commissioners, Company Size, Risk Monitoring Committee, and Financial Performance on Earnings Management

The purpose of this study is to find determinants of profit management (Earnings Management) such as the number of board of commissioners, the size of the company, the risk monitoring committee, and the financial performance of a company. The current study uses banking sector financial statement data recorded at Bank Indonesia (BI) with selective sampling methods that meet survey criteria. Researchers examined a period of five years using a sample of 120 data from 24 banking sector entities. The study used several methods of linear analysis with secondary data types. This study shows that the size of the board of commissioners, the size of the company, and the risk monitoring committee, and the ROA jointly affect profit management. The size of the board of commissioners and the size of the company individually do not indicate any influence on profit management. Individual risk monitoring committees affect profit management and ROAs individually have a positive influence on profit management.

Middle Cerebral Artery Aneurysm Trial (MCAAT): A Randomized Care Trial Comparing Surgical and Endovascular Management of MCA Aneurysm Patients

Whether the best management of middle cerebral artery (MCA) aneurysm patients is surgical or endovascular remains uncertain, with little evidence to guide decision-making. A randomized care trial offering MCA aneurysm patients a 50% chance of surgical and a 50% chance of endovascular management may optimize outcomes in the presence of uncertainty. The Middle Cerebral Artery Aneurysm Trial (MCAAT) is an investigator-initiated, multicenter, parallel group, prospective, 1:1 randomized controlled clinical trial. All adult patients with MCA aneurysms, ruptured or unruptured, amenable to surgical and endovascular treatment can be included. The composite primary outcome is "Treatment Success": (i) occlusion or exclusion of the aneurysm using the allocated treatment modality; (ii) no intracranial hemorrhage during follow-up; (iii) no retreatment of the target aneurysm during follow-up, (iv) no residual aneurysm on angiographic follow-up; and (v) independence (mRS <3) at 1 year. The trial tests 2 versions of the same hypothesis (one for ruptured and one for unruptured MCA aneurysm patients): Surgical management will lead to a 15% absolute increase in the proportion of patients reaching Treatment Success from 55% to 70% (ruptured) or from 75% to 90% (unruptured aneurysm patients) compared with endovascular treatment (any method). In this pragmatic trial, outcome evaluations are by treating physicians, except for 1-year angiographic results which will be core lab assessed. The trial will be monitored by an independent data safety monitoring committee to assure safety of participants. MCAAT is registered at clinicaltrials.gov: NCT05161377. Patients with MCA aneurysms can be optimally managed within a care trial protocol.

كلية الادارة والاقتصاد / جامعة صلاح الدين / اربيل

The research aims to diagnose the obstacles that hinder the implementation of the economic reform program in the Kurdistan Region - Iraq, with reference to the reasons for the failure of previous economic reform programs in the region, and to indicate the extent of citizens’ confidence in implementing the economic reform in the region, as well as evaluating the economic reform law of the new government for the year 2020. The research reached a set of results, including: 1- There is no time limit for implementing the economic reform process. 2- Efficient and specialized cadres in the field of economic reform were not relied upon when forming committees to implement economic reform decisions. 3- The absence of a monitoring committee to implement economic reform decisions. 4- The project did not extend to the national domain, and receded within the partisan domain. 5- Weak desire for real economic reforms on the part of the ruling parties. 6- The previous economic reforms project did not include all governorates in the Kurdistan Region, but was reduced to the governorates of Erbil and Dohuk. The research concluded by presenting a number of proposals, including: 1- It is the responsibility of the regional government to deposit all revenues, whether oil or non-oil revenues, in the banks affiliated with the Ministry of Finance and Economy. 2- Distributing a share (petro dollars) of the revenues of the Ministry of Natural Resources to the oil and gas producing areas, with the aim of enhancing services provided to citizens and raising the standard of living for the residents of these areas. 3- Activating the role of the Financial Supervision Bureau and the Integrity Commission in the Kurdistan Region. 4- Develop comprehensive planning for the development of all oil fields in a fair manner, without giving preference to the region over other regions

Heterologous SARS‐CoV‐2 vaccinations in patients with B‐cell lymphoid malignancies

Heterologous <scp>SARS‐CoV</scp>‐2 vaccinations in patients with B‐cell lymphoid malignancies

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy.

Background This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 105 cells/kg; medium-dose, 6.0 × 105 cells/kg; high-dose, 9.0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

Tre-P-16 - Phase II trial evaluating resminostat for maintenance treatment of patients with advanced stage (stage IIB–IVB) mycosis fungoides (MF) or Sézary syndrome (SS): RESMAIN study

<h3>Background:</h3> Patients with advanced CTCL disease ((stage IIB–IVB) mycosis fungoides (MF) or Sézary syndrome (SS)) have a poor prognosis and suffer from profound symptom burden. These patients require systemic treatment. However, it is still a key challenge to achieve durable remissions with the available treatment options. CTCL is characterized by the presence of malignant clonal T-cells in the skin and/or blood, lymph nodes or visceral organs. Epigenetic alterations in malignant T cells are known to play a key role in the pathogenesis of the disease. Resminostat is an orally available HDAC-inhibitor, which induces changes in gene expression resulting in growth inhibition, modified cell differentiation and enhanced tumor immunogenicity. The purpose of the RESMAIN study is to investigate resminostat as maintenance treatment for patients with advanced stage mycosis fungoides (MF) or Sézary syndrome (SS) that have achieved disease control with systemic therapy. <h3>Methods:</h3> The RESMAIN study is a multicenter, double blind randomized, placebo controlled, prospective efficacy trial. Patients are randomized 1:1 to the resminostat and the placebo arm. Furthermore, patients are stratified according to their remission status and their disease stage immediately prior to the last systemic therapy. Patients will be treated until disease progression. Patients of the placebo arm have the option to receive resminostat treatment. In addition, exploratory biomarker analyses will be performed. <h3>Results:</h3> The study is conducted in 11 European countries at 51 sites and at 5 sites in Japan. The first patient was enrolled in January 2017. Recruitment was impacted by the COVID-19 pandemic but continued slowly in 2020 and is now in its final stage. The independent data safety monitoring committee (DSMB) recommended continuation of the ongoing RESMAIN study without modification after a pre-specified review of cumulative safety data of the first 50, 100, ,150 and 175 patients which had completed at least one treatment cycle. The poster will present an actual status update of the RESMAIN study. <h3>Conclusion and objectives:</h3> The primary objective is to determine if maintenance treatment with resminostat increases progression free survival (PFS) compared to placebo. As a key secondary end point the effect of resminostat on time to symptom worsening (TTSW) of pruritus compared to placebo will be assessed. Further secondary endpoints are TTP, TTNT, ORR, OS and HrQoL among others. To our knowledge, this is the first randomized study that investigates the potential of an HDAC inhibitor as maintenance therapy in advanced CTCL.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure

In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. ClinicalTrials.gov Identifier: NCT02654327.

Dropless penetrating keratoplasty using a subconjunctival dexamethasone implant: safety pilot study

Background/aimRejection is the main cause of graft failure after penetrating keratoplasty (PK). Its prevention by repeated instillation of steroid eye-drops has not evolved in decades. Poor adherence and discontinuous nature...

Detailed statistical analysis plan for the short-term versus long-term mentalisation-based therapy for outpatients with subthreshold or diagnosed borderline personality disorder randomised clinical trial (MBT-RCT)

BackgroundPsychotherapy for borderline personality disorder is often extensive and resource-intensive. Mentalisation-based therapy is a psychodynamically oriented treatment option for borderline personality disorder, which includes a case formulation, psychoeducation, and group and individual therapy. The evidence on short-term compared with long-term mentalisation-based therapy is currently unknown.Methods/designThe Short-Term MBT Project (MBT-RCT) is a single-centre, parallel-group, investigator-initiated, randomised clinical superiority trial in which short-term (20 weeks) will be compared with long-term (14 months) mentalisation-based therapy for outpatients with subthreshold or diagnosed borderline personality disorder. Outcome assessors, data managers, the data safety and monitoring committee, statisticians, and decision-makers will be blinded to treatment allocation. Participants will be assessed before randomisation and at 8, 16, and 24 months after randomisation. The primary outcome will be the severity of borderline symptomatology assessed with the Zanarini Rating Scale for Borderline Personality Disorder. Secondary outcomes will be functional impairment (Work and Social Adjustment Scale), quality of life (Short-Form Health Survey 36—mental component), global functioning (Global Assessment of Functioning), and proportion of participants with severe self-harm. In this paper, we present a detailed statistical analysis plan including a comprehensive explanation of the planned statistical analyses, methods to handle missing data, and assessments of the underlying statistical assumptions. Final statistical analyses will be conducted independently by two statisticians following the present plan.DiscussionWe have developed this statistical analysis plan before unblinding of the trial results in line with the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice Guidelines, which should increase the validity of the MBT-RCT trial by mitigation of analysis bias.Trial registrationClinicalTrials.gov NCT03677037. Registered on 19 September 2018

Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection

Azithromycin has been hypothesized to have activity against SARS-CoV-2. To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14. Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization. Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92). The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21. Among 263 participants who were randomized (median age, 43 years; 174 [66%] women; 57% non-Hispanic White and 29% Latinx/Hispanic), 76% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50%; placebo: 50%; prevalence difference, 0%; 95% CI, -14% to 15%; P > .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4%; 95% CI, -1% to 9%; P = .16). Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection. ClinicalTrials.gov Identifier: NCT04332107.

Abstract CT104: Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety results of the INTR@PID LUNG 024 study

Abstract Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. The global, phase 1b/2 INTR@PID LUNG 024 (NCT03840915) study evaluates bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC. Here we report cumulative safety, which represents the first report of safety results from a clinical study with a bintrafusp alfa 2400-mg every-three-weeks (Q3W) regimen. Methods: Adults with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 are included. In cohorts A, B, and C, patients must not have received prior systemic therapy; in cohort D, patients must have had progression on previous anti-PD-(L)1 therapy. Patients received bintrafusp alfa 2400 mg Q3W intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or combination with pemetrexed in cohort A) for up to 31 cycles. The occurrence of dose-limiting toxicities (DLTs) was assessed during a 3-week observation period. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Additionally, in cohort A, patients from the safety and expansion parts will be assessed for preliminary efficacy. Results: As of October 7, 2020, 64 patients received bintrafusp alfa in combination with CT. Of the 35 patients included in the DLT analysis, 4 experienced 1 DLT according to the safety monitoring committee (A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). The cumulative safety is reported (Table). Conclusions: The combination of bintrafusp alfa 2400 Q3W in combination with CT was well tolerated. No new safety signals were identified. Cohort A (n=34)Cohort B (n=9)Cohort C (n=9)Cohort D (n=12)Treatment-emergent adverse events, n (%)Any*34 (100.0)9 (100.0)9 (100.0)12 (100.0)Grade ≥324 (70.6)6 (66.7)7 (77.8)12 (100.0)Grade ≥412 (35.3)3 (33.3)5 (55.6)6 (50.0)Serious22 (64.7)3 (33.3)6 (66.7)9 (75.0)Leading to death3 (8.8)1 (11.1)00Leading to dose reduction of CT9 (26.5)2 (22.2)5 (55.6)4 (33.3)Leading to permanent discontinuation of bintrafusp alfa12 (35.3)04 (44.4)4 (33.3)Leading to permanent discontinuation of CT13 (38.2)1 (11.1)4 (44.4)3 (25.0)Treatment-related adverse events, n (%)Any bintrafusp alfa-related adverse events28 (82.4)9 (100.0)9 (100.0)12 (100.0)Bintrafusp alfa-related serious adverse events9 (26.5)01 (11.1)3 (25.0)Bintrafusp alfa-related adverse events leading to death0000Any chemotherapy-related adverse events31 (91.2)8 (88.9)9 (100.0)12 (100.0)Chemotherapy-related serious adverse events10 (29.4)1 (11.1)4 (44.4)7 (58.3)Chemotherapy-related adverse events leading to death0000Adverse events of special interest, n (%)Skin lesions†2 (5.9)04 (44.4)1 (8.3)Immune-related adverse event15 (44.1)3 (33.3)5 (55.6)6 (50.0)Infusion-related reaction3 (8.8)1 (11.1)1 (11.1)1 (8.3)Anemia16 (47.1)5 (55.6)9 (100.0)9 (75.0)*Most common (≥50%) treatment-emergent adverse events in any cohort included anemia (cohort B: 55.6%; cohort C: 100.0%; cohort D: 75.0%), nausea (cohort A: 52.9%, cohort C: 66.7%), pruritus (cohort C: 66.7%), asthenia (cohort C: 55.6%; cohort D: 58.3%), neutropenia (cohort C: 55.6%), decreased appetite (cohort D: 50.0%), and diarrhea (cohort D: 50.0%).†Defined as actinic keratosis, basal cell carcinoma, Bowen's disease, hyperkeratosis, keratoacanthoma, lip squamous cell carcinoma, and squamous cell carcinoma of skin. Actinic keratosis, hyperkeratosis, and keratoacanthoma were reported in this study. Citation Format: Christian Rolfo, Laurent Greillier, Remi Veillon, Firas Badin, Francois Ghiringhelli, Nicolas Isambert, Astrid Paulus, Marc Lambrechts, Italia Grenga, Xiaoli You, Andre Koenig, Sandrine Hiret. Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety results of the INTR@PID LUNG 024 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT104.

Efficacy of Intraoperative Neuromonitoring Using Transcranial Motor-Evoked Potentials for Degenerative Cervical Myelopathy: A Prospective Multicenter Study by the Monitoring Committee of the Japanese Society for Spine Surgery and Related Research.

A prospective multicenter observational study. To elucidate the efficacy of transcranial motor-evoked potentials (Tc(E)-MEPs) in degenerative cervical myelopathy (DCM) surgery by comparing cervical spondylotic myelopathy (CSM) to cervical ossification of the posterior longitudinal ligament (OPLL) and investigate the timing of Tc(E)-MEPs alerts and types of interventions affecting surgical outcomes. Although CSM and OPLL are the most commonly encountered diseases of DCM, the benefits of Tc(E)-MEPs for DCM remain unclear and comparisons of these two diseases have not yet been conducted. We examined the results of Tc(E)-MEPs from 1176 DCM cases (840 CSM /336 OPLL) and compared patients background by disease, preoperative motor deficits, and the type of surgical procedure. We also assessed the efficacy of interventions based on Tc(E)-MEPs alerts. Tc(E)-MEPs alerts were defined as an amplitude reduction of more than 70% below the control waveform. Rescue cases were defined as those in which waveform recovery was achieved after interventions in response to alerts and no postoperative paralysis. Overall sensitivity was 57.1%, and sensitivity was higher with OPLL (71.4%) than with CSM (42.9%). The sensitivity of acute onset segmental palsy including C5 palsy was 40% (OPLL/CSM: 66.7%/0%) whereas that of lower limb palsy was 100%. The most common timing of Tc(E)-MEPs alerts was during decompression (63.16%), followed by screw insertion (15.79%). The overall rescue rate was 57.9% (OPLL/CSM: 58.3%/57.1%). Since Tc(E)-MEPs are excellent for detecting long tract injuries, surgeons need to consider appropriate interventions in response to alerts. The detection of acute onset segmental palsy by Tc(E)-MEPs was partially possible with OPLL, but may still be difficult with CSM. The rescue rate was higher than 50% and appropriate interventions may have prevented postoperative neurological complications.Level of Evidence: 3.

Abstract CT217: Phase I, first-in-human trial evaluating BI 1387446 (STING agonist) alone and in combination with ezabenlimab (BI 754091; anti-PD-1) in solid tumors

Abstract Background/Purpose Activation of the stimulator of interferon genes (STING) pathway in intratumoral immune cells leads to increased type I interferon production, promoting recruitment and priming of T-cells against tumor antigens and triggering anti-tumor activity. In patients with cancer, STING agonists have shown clinical activity, with effects increased when combined with an anti-programmed cell death [PD]-1 antibody. BI 1387446 potently and highly selectively activates the STING pathway; ezabenlimab (BI 754091) is a humanized IgG4 anti-PD-1 monoclonal antibody. Tumor regression and enhanced activity of anti-PD-1 therapy was observed after BI 1387446 administration in syngeneic tumor models. Methods NCT04147234 is a first-in-human, Phase I, open-label, multicenter trial of BI 1387446 recruiting a planned 122 patients from six sites across Europe and the USA. Patients will have advanced, unresectable and/or metastatic solid tumors. The main objectives are to characterize safety and determine the maximum tolerated dose (MTD) of BI 1387446 alone and in combination with ezabenlimab. BI 1387446 will be administered intratumorally at escalating doses as monotherapy in Arm A (~34 patients), and + ezabenlimab (240 mg every 3 weeks, IV) in Arm B (~44 patients); BI 1387446 will be administered in superficial lesions in both Arms. In a potential Arm C (~44 patients), BI 1387446 will be administered in deep/visceral lesions + ezabenlimab, IV. Arm B will open at the starting dose level once the starting dose level in Arm A is considered safe by the safety monitoring committee; Arm C may open at the starting dose level once this dose level is considered safe in Arm B. Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. Patients (≥18 years of age) must have exhausted standard treatment options, have ≥1 tumor lesion suitable for injection, ≥1 additional tumor lesion amenable to biopsy, and ECOG performance status ≤1. Treatment will continue until progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum of 34 cycles (for cycles 19–34, only patients with partial response will receive BI 1387446), whichever occurs first. Primary endpoints are the MTD based on number of dose-limiting toxicities (DLTs) and number of patients with DLTs. Secondary endpoints are objective response rate (based on RECIST 1.1 criteria) and best change from baseline in size of target and injected (and uninjected) lesions. Plasma, blood, and tumor tissue will be collected at baseline and on-therapy for pharmacodynamic analyses. The trial is actively recruiting, and eight patients have been treated as of December 2020. Citation Format: Kevin Harrington, Eileen Parkes, Jared Weiss, Mathew Ingham, Andrés Cervantes, Emiliano Calvo, Ute Klinkhardt, Patricia Sikken, Michael Schmohl, Elena Garralda. Phase I, first-in-human trial evaluating BI 1387446 (STING agonist) alone and in combination with ezabenlimab (BI 754091; anti-PD-1) in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT217.

Abstract CT234: VASTUS - a phase 1b/2a basket trial of a new PARP inhibitor, IDX-1197, including PARP inhibitor resistant cohort

Abstract [BACKGROUND]Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or germline or somatic homologous recombinant repair mutation (g/sHRRmt), and advanced serous ovarian cancer that are homologous recombination deficiency (HRD)-positive, g/sBRCAmt or sensitive to prior platinum treatment. However, there is limited knowledge about the efficacy of PARP inhibitors in other cancers with HRD with or without gBRCAmt, in platinum-resistant settings, and about efficacy after prior PARP inhibitor treatment. IDX-1197 is a new PARP inhibitor which is active against cell lines with acquired resistance to platinum and PARP inhibitors. VASTUS study is a basket trial composed of 9 different cohorts investigating use of IDX-1197 in various tumors known to be responsive to PARP inhibitors, as well as in tumors and settings that have not been well-investigated so far. [METHOD]VASTUS is a multi-center, basket trial (NCT04174716) to evaluate safety and efficacy of IDX-1197 as a monotherapy in 1) cancers that are known to be responsive to PARP inhibitors (breast cancer, ovarian cancer, and pancreatic cancer), 2) cancers where PARP inhibitors' safety and efficacy have not been confirmed (small cell lung cancer, biliary tract cancer, uroepithelial cancer, and gastric cancer), 3) any solid tumors resistant to prior platinum-based therapy, excluding refractory to prior platinum based therapy, and 4) any solid tumors that have been exposed to prior PARP inhibitors. In VASTUS trial, patients are selected by pathogenic mutations in HRD-related genes. In the cohort for tumors with prior exposure to PARP inhibitors, patients are eligible regardless of gene mutations as long as they have received prior PARP inhibitor. Study is composed of two parts – phase 1b to assess safety and tolerability of IDX-1197 and to determine recommended phase 2 dose; after review by data safety monitoring committee and go/no-go decision, phase 2a will be commenced to assess the efficacy of IDX-1197 based on objective response rate (ORR). Retrospective translational researches with tumor tissue and peripheral blood are planned (circulating tumor DNA), specifically for prior PARP inhibitor exposure cohort. As of 05 Jan 2021, 32 patients have been enrolled. Citation Format: Kyung-Hun Lee, Ahrum Min, Hee Kyung Ahn, Keun Seok Lee, Yong Wha Moon, Seung Tae Kim, Jeong Eun Kim, Joo Hyuk Sohn, Il Hwan Kim, Woo Kyun Bae, Myong Jae Lee, Eun-Jihn Roh, Chan-Young Ock, Won Sik Lee, Seock-Ah Im. VASTUS - a phase 1b/2a basket trial of a new PARP inhibitor, IDX-1197, including PARP inhibitor resistant cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT234.

Financial performance: Does Board Monitoring Committees Matter? An Empirical Analysis of Listed Building Material Companies in Nigeria

This study examines the association between the monitoring committee of the board and the financial performance of listed building materials companies in Nigeria for the period 2008-2018. The study population is 15 listed building materials companies in Nigeria, out of which a sample of 11 utilized due to non-accessibility and unavailability of data. The independent variable was board monitoring committees proxies by the executive committee, finance and general-purpose committee, nomination and remuneration committee and statutory audit committee, while return on assets (ROA) used to measured financial performance. Data collected from a secondary source through the annual reports and accounts of building materials companies for the period under review. The ordinary least square (OLS) regression techniques employed for data analysis. The finding reveals a positive and significant association between executive committee, statutory audit committee and financial performance, while shows a negative and significant relationship between nomination and remuneration committee and financial performance. The study recommends that board monitoring committees: the executive committee should increase to the maximum of 5 members, the statutory audit committee should increase from 6 to 8 members, nomination and remuneration should decrease to the maximum of 5 members for all building materials companies operating in Nigeria.

The parties and the nature of the second level agreement governing the "adapted subordination" of riders employed by Just Eat - Takeaway.com Express Italy

The article discusses the legal nature of the second-level company contract signed by Takeaway.com Express with the Confederal Transport Associations. It also dwells on the parties to the agreement, highlighting the absence of metropolitan unions among the signatories. Lastly, he describes the operation of the bilateral monitoring committee, which is responsible for making adjustments to the contract.