Part A1 Research Articles

Pharmacodynamic (PD) and immunophenotyping analyses of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib in a phase Ib study in patients with advanced unresectable solid tumors.

2612 Background: Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases orchestrate the DNA damage response. A synthetic lethal relationship between ATR and ATM genes in cancer has been described1 and ATMi synergistically potentiate the efficacy of ATRi in vitro and in vivo.2 The combination of tuvusertib + lartesertib was investigated in Part A1 of the open-label, multicenter study DDRiver Solid Tumors 320 in patients with advanced unresectable solid tumors. Here, we report results of the PD and immunophenotyping analyses. Methods: PD analysis comprised γ-H2AX in serial blood samples, stimulated ex vivowith 4-NQO, bleomycin, or controls. Flow cytometry was used to measure target inhibition via γ-H2AX modulation in the CD45+ lymphocytes fraction and to explore the effect of tuvusertib + lartesertib on the immunophenotype (myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells subsets) in serial blood samples. Pharmacokinetic samples were analyzed by a validated bioanalytical liquid chromatography/mass spectrometry method. Time-matched blood samples were collected at baseline, 1, 3, 6, and 24 hours after first tuvusertib and lartesertib administration on days 1 and 8 of cycle 1 for the γ-H2AX analysis, and on days 1 and 15 of cycles 1 and 2 before treatment for immunophenotyping. Results: Immunophenotyping data and γ-H2AX levels were obtained from 41 and 34 patients, respectively. For tuvusertib, complete or almost complete target inhibition was seen at 1–6 hours after treatment, followed by a rebound above baseline after 24 hours, on both days 1 and 8 at doses of 130 and 180 mg once daily (QD). For lartesertib, a variable target inhibition of approximately 50 % on average was seen across all time points at doses of 100, 150 and 200 mg QD. No target inhibition was seen for tuvusertib at 90 mg QD and lartesertib at 50 mg QD (cohort 1). Tuvusertib + lartesertib induced a transient decrease of monocytes and natural killer (NK) cells, with partial or complete recovery to baseline levels during treatment breaks in schedules of 2 weeks on treatment followed by a treatment break of 1 or 2 weeks, respectively. Conclusions: Tuvusertib and lartesertib combination PD outcomes were in line with respective monotherapy observations.3,4 The combination did not cause any consistent change in the levels of immune cell subsets at all dose levels tested, except a mild, transient decrease in monocytes and NK cells, in line with the tuvusertib monotherapy observations. 1. Kantidze et al., Trends Cancer 2018;4(11):755–68. 2. Turchick et al., Mol Cancer Ther 2023;22(7):859–72. 3. Yap et al., Ann Oncol 2022;33(suppl_7):S197–S224. 4. Siu et al., Cancer Res 2023;83(8_Suppl):CT171. Clinical trial information: NCT05396833 .

Takeaim Lymphoma: An Open-Label, Dose Escalation and Expansion Trial of Emavusertib (CA-4948) in Combination with Ibrutinib in Patients with Relapsed or Refractory Hematologic Malignancies

Background: Emavusertib (CA-4948) is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. Additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4) is also present in emavusertib. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation ofnuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) (Nowakowski 2020). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. Emavusertib crossed the blood-brain barrier in a murine PDX model of PCNS lymphoma, blocked the activated IRAK4 pathway, and induced tumor response and prolonged survival (von Roemeling 2022). In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vitro synergy and re-sensitization of resistant cell lines, overcoming BTK resistance (Guidetti 2023a and 2023b). In vivo synergy in B-cell NHL was also demonstrated. Adaptive chemotherapy treatment resistance through IRAK4 upregulation and activation was also described in other disease models (Melgar 2019, Li 2019). This abstract presents preliminary efficacy and safety data of emavusertib + ibrutinib in R/R NHL patients. Aim:Assessment of safety and clinical activity of emavusertib in combination with ibrutinib. Methods: This is an ongoing open-label trial (NCT03328078) of emavusertib as monotherapy and in combination with ibrutinib. Part A1 - completed; dose escalation of emavusertib as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing (Nowakowski 2020). Part A2 - completed; dose escalation of emavusertib in combination with ibrutinib at 420 and 560 mg QD (Joffe 2022). Part B - ongoing; an expansion cohort of PCNSL patients with resistance to prior BTK inhibitors for additional safety and efficacy related to exposure: emavusertib at 100 or 200 mg BID + ibrutinib at 560 mg QD in 28-Day cycles. Results:As of 19 July 2023, 18 heavily pretreated NHL (including five PCNSL) patients received emavusertib at 100, 200, or 300 mg BID in combination with full ibrutinib doses per label. Median age was 63.5 years (range 50-92). Median number of prior lines of anti-cancer therapies was 3 (range 1-10). Eleven of 18 patients failed prior BTK inhibitors. Median treatment duration was 95.5 days (21-587 days), suggesting acceptable safety and tolerability. No DLTs were observed at the 200 mg BID dose level, and two reversible DLTs (stomatitis and syncope) were observed at the 300 mg BID dose level. The preliminary efficacy data of 16 evaluable patients in combination with ibrutinib showed 5 CRs (2 MCL, 3 PCNSL) and 1 PR (1 CLL). All 3 PCNSL patients with CR were previously treated with BTK inhibitors. Conclusion: The combination ofemavusertib plus ibrutinib (ema+ibr) is well tolerated with an acceptable long-term safety profile and promising efficacy, showing several objective responses in heavily pretreated and/or BTK inhibitor resistant patients. Emavusertib may have the potential to overcome BTK inhibitor resistance and the combination of ema+ibr has the potential to show increased anti-cancer activity compared to ibrutinib monotherapy.

Teknik Permainan Appogiatura Piano Pada Lagu “Waltz In A Minor, B.150, Op.Posth” Karya Frederic Chopin

This research aims to determine the techniques for playing appogiatura piano in the song "Waltz in a minor, B.150, Op.Posth" by Frederic Chopin. The author uses descriptive qualitative methods. The object of this research is the score for Waltz in a minor, B.150, Op.Posth" by Frederic Chopin. The data analysis techniques used are data reduction, data presentation, and data conclusions. The results and discussion of this research are Frederic Chopin's "Waltz in a minor, B.150, Op. Posth" which is a solo performance that uses playing techniques such as Appoggiatura and is equipped with techniques such as mordent, trill, triplet-quintuplet, and legato, as well as dynamics so that what is produced in part A1, wants to describe a sad atmosphere because of the legato technique which makes it lilting, then in part B with appoggiatura and legato techniques wants to describe a cheerful atmosphere as if there is hope, supported by a Major chord at the beginning, variations melodies, and lots of appoggiatura, triplet-quintuplet ornaments as sweeteners. Next, section A' again depicts a sad atmosphere, but the modulation to A Major makes hope even more visible. But in section A2, the sweet dance atmosphere, the hopes built in sections B and A' return to an atmosphere of sadness which then in the Coda section ends with an ornamental trill at the end of the song so that it can depict an atmosphere of decline.

Abstract CT094: Phase I dose-escalation study evaluating the safety and tolerability of ginisortamab (UCB6114), a first-in-class anti-gremlin-1 monoclonal antibody (mAb), as monotherapy in advanced solid tumors

Abstract Effective treatment for gastrointestinal (GI) cancers is a significant unmet need. Gremlin-1, secreted by cancer-associated fibroblasts, downregulates bone morphogenetic proteins (BMP), members of the transforming growth factor β superfamily, resulting in tumor stemness, hyperproliferation, and invasiveness. Ginisortamab, a fully human IgG4P mAb, neutralizes gremlin-1, thus restoring BMP signaling. Preclinical studies showed that ginisortamab binds to gremlin-1 and has antitumor activity in several mouse models, including GI cancers. Here we report the initial findings from Part A (monotherapy dose escalation) of the first-in-human study. ONC001 (NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study assessing the safety, PK/PD, and antitumor activity of intravenous (IV) ginisortamab as monotherapy or in combination with selected standard of care regimens in patients (pts) with advanced solid tumors. ONC001 includes 3 dose escalation modules (Parts A-C) and a dose adaptation module (Part A1). To be eligible for Part A, pts had to be aged ≥18 years (y) with advanced disease, resistant or refractory to standard therapy, with ECOG PS ≤1. We present the primary (safety, tolerability), secondary (PK/PD), and exploratory (antitumor activity) endpoints, as well as the monotherapy RP2D from Part A. At data cutoff (June 20, 2022), 25 pts received ≥1 dose of ginisortamab (median [range] age: 64 [37-74] y; 68% male; 88% White; 36% had >3 lines of prior therapy). The most common tumor type enrolled was colorectal adenocarcinoma (44%). Ginisortamab was escalated using a modified rolling 6 design through 5 levels (100, 250, 500, 1000, and 2000 mg IV Q2W) in 28-day cycles. No DLTs, Grade ≥3 AEs related to ginisortamab, or serious related AEs were observed; the 2000 mg dose was deemed safe for further development. Temporary treatment interruption and study discontinuation due to AEs unrelated to ginisortamab occurred in 7 (28%) and 2 pts (8%), respectively. Ginisortamab PK aligned with expectations from preclinical models for an IgG4 mAb, allowing favorable dosing intervals. Confirmation of target occupancy was demonstrated by increases in total circulating gremlin-1. Antidrug antibody formation was not observed. The best overall response of stable disease was observed in 7/24 pts (29%); 4 pts had a reduction of the sum of the dimensions of their target lesions relative to baseline. Favorable safety and PK/PD data at the maximum dose of 2000 mg and preliminary antitumor activity were observed with the first-in-class anti-gremlin antibody ginisortamab. These data support further evaluation of the efficacy and safety of ginisortamab monotherapy at 2000 mg Q2W, or in combination with standard of care regimens (FOLFOX, trifluridine/tipiracil) in advanced solid tumors. Citation Format: Debashis Sarker, Sarah Blagden, Natalie Cook, Thomas R. Evans, Ruth Plummer, Angelos Angelakas, Saira Bashir, Salma El Badri, Leonidas Mavroeidis, Cienne Morton, Abdul (Moe) Muhith, Mark White, Rupert Dixon, Elodie Garric, Joanne Mann, Ivan Matthews, Udai Banerji. Phase I dose-escalation study evaluating the safety and tolerability of ginisortamab (UCB6114), a first-in-class anti-gremlin-1 monoclonal antibody (mAb), as monotherapy in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT094.

Abstract CT272: Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301)

Abstract Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated in Part A1 of an open-label, single-arm study (NCT04170153) for safety, tolerability, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). M1774 monotherapy in patients with advanced solid tumors was well-tolerated and the totality of evidence, including quantitative model-based analyses, suggested the recommended dose for expansion (RDE) as 180 mg QD 2 weeks on/1 week off.1 Here, we report findings of the M1774 PD and immunophenotyping analyses. Methods: M1774 PD was explored by assessing phosphorylation by ATR of CHK1 (p-CHK1) in tumor and of H2AX (γ-H2AX) in serial blood samples, stimulated ex vivo with the radiomimetic 4-Nitroquinoline N-oxide or Dimethyl sulfoxide as control. A flow cytometry quantitative assay was used to measure γ-H2AX in the CD45+ lymphocytes fraction. The effect of M1774 on the immunophenotype was explored by flow cytometry. Blood samples were collected at baseline, 3 and 24 hours after first M1774 administration on day 1 of cycle 1 for the γ-H2AX analysis, and on Days 1 and 15 of Cycles 1 and 2 before treatment for immunophenotyping. Results: Preclinical tumor tissue-blood bridging PD analyses in a mouse model demonstrated that the inhibition of γ-H2AX in lymphocytes highly correlated with inhibition of p-CHK1 in tumor. Clinical data of γ-H2AX levels and immunophenotyping were generated for the blood samples collected from the 55 participants of Part A1 of the study. Exploratory PK-PD analysis using γ-H2AX levels 3 h post-dose on day 1 across the doses predicted target inhibition >80% for doses ≥130 mg, suggesting target engagement. The levels of ɣ-H2AX at 24 h after first dose intake were variable and mean levels rebounded to baseline value. M1774 treatment did not cause any significant and consistent change in the levels of all explored immune cell subsets at the tested dose levels, including myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells. Conclusions: PD analyses showed that M1774 efficiently inhibited ATR at the RDE without impacting the immunophenotype. 1TA Yap, et al. Ann Oncol. 2022; 33(suppl_7): S197-S224. Citation Format: Ruth Plummer, Anthony W. Tolcher, Timothy A. Yap, Giuseppe Sessa, Jatinder K. Mukker, Annick Seithel-Keuth, Christine Hicking, Zoltan Szucs, Ioannis Gounaris, Giuseppe Locatelli, Johann S. de Bono. Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT272.

Restructuring moratoriums through an information-processing lens

ABSTRACT Using insights from complex systems theory, it is argued that financially distressed large corporates will seek the protection of a moratorium when the benefits it brings outweigh its signalling and information-processing problems – likely to be in the later stages of distress. Applying this insight, the article offers a somewhat gloomy assessment of the Part A1 moratorium introduced in the UK by the Corporate Insolvency and Governance Act 2020. It is suggested that the UK administration moratorium may be more fit for purpose, but that serious signalling and information processing concerns remain. After touching on possible adaptations of the tools, the article concedes that there may have been a deliberate decision to restrict the usefulness of both of them. The article ends by arguing that if this the case, the decision may not be sustainable in a rapidly changing economic environment, and that recent suggestions for reform should be supported.

457MO A phase I study of ATR inhibitor M1774 in patients with solid tumours (DDRiver Solid Tumours 301): Part A1 results

Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor, exerts antitumour activity in preclinical models.

Life Cycle Environmental and Cost Analysis of Building Insulated with Hemp Fibre Compared to Alternative Conventional Insulations – a Swedish Case Study

This study presents a comparative life cycle analysis (LCA) and life cycle costing (LCC) assessments of hemp fibre and conventional alternative insulations for the climate shell of a building. The conventional alternative insulations compared to the hemp fibre are cellulose and glass wool. The object of the analysis is a one-story single-family house, in Växjö, Sweden, and the lifetime of the house is set to 50 years. The LCA focuses on the Global Warming Potential (GWP) impact and the LCC during the lifetime of the different insulations for the building are calculated using the net present value method. The results show that the net GWP-impact for hemp fibre insulation is about 10 % lower and the cost is about 20 % higher than the conventional glass wool alternative. Furthermore, the analysis shows that cellulose insulation has slightly lower GWP-impact and nearly the same cost as the glass wool alternative. Sensitivity analyses regarding five different issues were performed and these show that: for cellulose coming from recycled paper, it contributed to less fossil emissions than non-recycled paper. If the data source for glass wool insulation is changed from environmental product declarations (EPD) to generic data, the greenhouse gas emissions increased. By replacing district heating system with geothermal heating system, fossil GWP-impacts also increased while the LCC analysis shows that operating costs is reduced. If the fuel is changed from diesel to electricity, fossil emissions are reduced over the life cycle of the building. If only part A1 – A5 is reported, as required for the Swedish climate declaration, the results point to the outcomes that glass wool insulation gives the least fossil GWP-impact while the hemp fibre gives the least net GWP-impact.

Abstract CT248: Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF- and NRAS-mutation positive solid tumors

Abstract Background: BRAFV600 alterations (BRAF Class (Cl) I alterations) encode a highly active monomeric oncogenic kinase that can be targeted by approved RAF kinase inhibitors (RAFi) in patients (pts) with melanoma (MEL), NSCLC, colorectal & anaplastic thyroid cancers. Cl II and III represent molecularly distinct BRAF alterations driving dimer-dependent signaling. Cl II alterations include single nucleotide variants (SNVs), indels and gene fusions that induce BRAF homodimer formation, leading to oncogenic kinase activation. Cl III alterations, typically SNVs, are low activity alterations that promote RAF dimerization and RAS-dependent oncogenic MAPK pathway signaling. Approved BRAFi have limited clinical activity in solid tumors driven by BRAF Cl II or III alterations, highlighting the urgency to develop effective targeted therapies for these patients. Combinations of a RAFi and a MEK inhibitor (MEKi) show promising results in early clinical trials. KIN-2787 is a potent, highly selective type II pan-RAFi designed to target both monomeric & dimeric forms of the altered BRAF kinase and minimize paradoxical activation, a liability often observed with other RAFi that can adversely impact tolerability & require addition of a MEKi to suppress pathway activation. KIN-2787 has favorable pharmaceutical properties, achieves substantial systemic exposures in pre-clinical toxicology studies, & induces regressions in human cancer xenograft models driven by BRAF Cl I, II, or III alterations. Combinations of KIN-2787 with a MEKi show promising activity in preclinical models. Methods: This is a FIH, multicenter, non-randomized Ph1 study (NCT04913285) of KIN-2787 in adult pts with BRAF mutant advanced & metastatic solid tumors (AMST). KIN-2787 will be given orally bid continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approx. 155 pts in 2 parts: Part A is a dose-escalation to MTD open to pts with AMST driven by either BRAF genomic alterations (Cl I, II or III ) or by NRAS. Part A1 assesses single agent KIN-2787; Part A2 assesses KIN-2787 in combination w/binimetinib. Part B will evaluate a selected dose of KIN-2787 in 3 cohorts of pts (MEL, NSCLC, or other AMST), each driven by BRAF Cl II or III alterations. Standard Ph1 enrollment criteria are required (ECOG PS 0-2, normal organ function, prior receipt of standard treatment or medical judgment that such is not appropriate). Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases, prior BRAF-, MEK-, or MAPK inhibitor therapy (unless for FDA approved indications), HBV/HCV seropositivity. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, & duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of MAPK signaling inhibition. Enrollment began in August 2022. Trial is open globally. Citation Format: Meredith McKean, Cesar A. Perez, Shumei Kato, Alexander I. Spira, Yan Xing, Hao Xie, Michael Millward, Anthony Olszanski, Ken Kobayashi, Nichol Miller, Paul Severson, Betty Tam, Caro Unger. Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF- and NRAS-mutation positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT248.

Open-label, dose-escalation, and expansion trial of CA-4948 in combination with ibrutinib in patients with relapsed or refractory hematologic malignancies.

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: study protocol for the randomised controlled phase II ReSScue trial

IntroductionIn the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the negative impact is substantial. Aiming for...

A first-in-human phase I study of ATR inhibitor M1774 in patients with solid tumors.

TPS3153 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response by sensing and responding to DNA replication stress, and by inducing cell cycle arrest to prevent aberrant replication and mitotic catastrophe. Based on extensive preclinical and limited clinical evidence, ATR inhibition is a promising treatment strategy as monotherapy for patients with advanced tumors harboring synthetically lethal conditions, such as alternative lengthening of telomeres (ALT) and inactivating mutations in ARID1A and ATM. M1774 is a potent, selective, orally administered ATR inhibitor that has been shown to exert antitumor activity in patient-derived xenograft tumors and acute myeloid leukemia xenograft tumors that express the ATR inhibition sensitizing mixed lineage leukemia fusion protein. This study (NCT04170153) aims to evaluate the safety and tolerability, maximum tolerated dose, recommended dose for expansion (RDE) and pharmacokinetics (PK) of M1774 (part A1), the effect of food on M1774 PK (part A2), and the efficacy of M1774 in patients with tumors harboring selected mutations (part A3). An additional objective is to assess the pharmacodynamics of M1774 by measuring relative changes in baseline p-CHK1 and γ-H2AX expression in paired tumor biopsies and serial blood samples. Methods: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status ≤1, adequate baseline hematological, renal and hepatic function, and with locally advanced or metastatic disease refractory to standard therapy are eligible. Patients with tumors bearing loss-of-function (LoF) mutations (determined by site testing or a central trial assay) in ARID1A, ATM, or ATRX and/or DAXX as ALT status surrogate markers; and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, will be enrolled in part A3. In the dose escalation phase (part A1 [open]), 18–24 patients are due to receive M1774 at a starting dose of 5 mg once daily. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. The preliminary food assessment (part A2) will follow a randomized two-sequence two-period crossover design in which ≤12 patients will be randomized (1:1) to receive a single dose of M1774 on Day –7 at the RDE (determined in part A1) in either a fed or fasted condition. After the food assessment, patients will subsequently receive M1774 according to the part A1 dosing schedule. In the preliminary efficacy study (part A3), patients (n = 20–24 for each of the three planned cohorts) with tumors harboring LoF mutations in the genes for ARID1A, ATM, ATRX and/or DAXX, will receive M1774 at the RDE. The primary efficacy endpoint is overall response (RECIST). The study is open and currently recruiting. Patients have been enrolled to seven cohorts in part A1 with no DLTs observed; dose escalation is ongoing. Clinical trial information: NCT04170153.

First-in-human phase 1 trial (DRAGON) of SRK-181, a potential first-in-class selective latent TGFβ1 inhibitor, alone or in combination with anti-PD-(L)1 treatment in patients with advanced solid tumors.

TPS3146 Background: Transforming growth factor-beta 1 (TGFβ1) is a key mediator of primary resistance to programmed cell death protein 1 (PD-1) pathway blockade. SRK-181 is a fully human, highly potent and selective monoclonal antibody that inhibits latent TGFβ1 activation. SRK-181 has minimal or no binding to latent TGFβ2 and TGFβ3 isoforms or to active TGFβ growth factors. In mouse tumor models (bladder, melanoma, and breast cancer), SRK-181 in combination with anti-PD1 therapy overcame primary anti-PD-1 resistance and showed survival benefit. No cardiotoxicities (valvulopathy) were observed with SRK-181 in 4-week GLP nonclinical toxicology studies. Thus, the potency and selectivity of SRK-181 may overcome PD-1 inhibitor resistance and toxicity of non-selective TGFβ pathway approaches. Methods: The DRAGON trial NCT04291079 is an ongoing multicenter, open-label, phase 1 study of SRK-181 administered by IV infusion every 3 weeks (Q3W) alone or in combination with anti-PD-(L)1 in patients (pts) with locally advanced or metastatic solid tumors. The study comprises 3 parts: Part A of the study follows a standard 3+3 dose escalation trial design to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of SRK-181 alone (Part A1) or in combination with the anti-PD-(L)1 agent that is approved for the respective tumor indication (Part A2). Part A1 and Part A2 will determine maximum tolerated dose (MTD) or maximum administered dose and Recommended Phase 2 Dose (RP2D) for Part B. Part B (expansion phase) will evaluate combination treatment of SRK-181 with anti-PD-(L)1 in pts with non-small cell lung cancer, urothelial carcinoma (UC), melanoma or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the antitumor activity of combination treatment. Pts in Part A2 and Part B must have previously received an anti-PD-(L)1 therapy approved in their tumor indication and considered non-responders (best response of stable disease or disease progression) to anti-PD-(L)1 monotherapy. Pts in Part B must have received the most recent dose of the prior anti-PD-(L)1 within 6 months of study enrollment (9 months for UC cohort). Safety, PK, PD and efficacy data will be collected and monitored throughout the study. Detailed translational PD and predictive biomarker studies for SRK-181 will include a novel digital pathology analysis of CD8 to assess the alteration of immune profile in tumor microenvironment and TGFb pathway biomarkers, such as quantitative analysis of tumor phospho-Smad2 and circulating levels of TGFb1 ligand. As of Feb 01 2021, dose escalation has proceeded to the highest planned dose of 2400 mg Q3W in Part A1 (monotherapy) and to 800 mg Q3W in Part A2 (anti-PD-(L)1 combination). Additional planned doses in Part A2 are 1600 mg and 2400 mg Q3W. Clinical trial information: NCT04291079.

ANALISIS BENTUK DAN STRUKTUR MUSIK PROGRAMA DANSE MACABRE KARYA CAMILLE SAINT-SAENS

The study aims to analyze the shape and musical structure of Camille Saint-Saens's "Danse Macabre" programa, which looks at the extra elements of musicals and Intra musicals as a whole. This study uses a musical approach and the results are qualitative. The main instruments in this study are the researchers themselves. Data collection techniques are done by means of library studies and observations. The steps to analyze data are to collect data, describe data, analyze and make conclusions. The results showed that Danse Macabre is a free form of music composition in which this form of music is irregular/bound to any form of music seen working on melodies that flow just like that based on the story the composer describes can be seen based on the extramusical and intra musical elements. The integrity of Danse Macabre's programa music work is formed from the Intro section, part A, part B, part A1, part A2, part B1, part B2, part A3, part C, part C1, part A+B, and the Coda section with the kadens on the last two seasons. Introduction tells the story of the midnight time played by Harp, resulting in the sound of clocks that signify the day at exactly 00:00 or midnight and the Grimp Reaper begins summoning ghosts to party and dance.Keywords: Shape Analysis, Danse Macabre, Camille Saint-Saens

A Multi-Center, Dose-Finding Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of a Novel IRAK4 Inhibitor CA-4948 in Combination with Ibrutinib, in Patients with Relapsed or Refractory Hematologic Malignancies

A Multi-Center, Dose-Finding Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of a Novel IRAK4 Inhibitor CA-4948 in Combination with Ibrutinib, in Patients with Relapsed or Refractory Hematologic Malignancies

Efficacy and Safety of Continuous Risankizumab Therapy vs Treatment Withdrawal in Patients With Moderate to Severe Plaque Psoriasis

Risankizumab selectively inhibits interleukin 23, a cytokine that contributes to psoriatic inflammation. To evaluate the efficacy and safety of risankizumab vs placebo and continuous treatment vs withdrawal in adults with moderate to severe plaque psoriasis. Multinational, phase 3, randomized, double-blind, placebo-controlled trial conducted from March 6, 2016, to July 26, 2018. A total of 507 eligible patients had stable moderate to severe chronic plaque psoriasis for 6 months or longer, body surface area involvement greater than or equal to 10%, Psoriasis Area and Severity Index (PASI) greater than or equal to 12, and a static Physician's Global Assessment (sPGA) score greater than or equal to 3. Intention-to-treat analysis was conducted. Patients were randomized (4:1, interactive response technology) to risankizumab, 150 mg, subcutaneously, or placebo at weeks 0 and 4 (part A1). All patients received risankizumab at week 16. At week 28, patients randomized to risankizumab who achieved an sPGA score of 0/1 were rerandomized 1:2 to risankizumab or placebo every 12 weeks (part B). Co-primary end points for the part A1 phase included proportions of patients achieving greater than or equal to 90% improvement in PASI (PASI 90) and sPGA score of 0/1 at week 16. The PASI measures severity of erythema, infiltration, and desquamation weighted by area of skin involvement over the head, trunk, upper extremities, and lower extremities; scores range from 0 (no disease) to 72 (maximal disease activity). The sPGA assesses average thickness, erythema, and scaling of all psoriatic lesions; scores range from 0 (clear) to 4 (severe), with 0/1 indicating clear or almost clear. Primary and secondary end points in part B included proportion of rerandomized patients achieving an sPGA score of 0/1 at week 52 (primary) and week 104 (secondary). Of 563 patients screened, 507 were randomized to risankizumab (n = 407) or placebo (n = 100). Most patients were men (356 [70.2%]); median age was 51 years (interquartile range, 38-60 years). At week 16, 298 patients (73.2%) in the treatment group vs 2 patients (2.0%) receiving placebo achieved a PASI 90 response, and 340 patients (83.5%) receiving risankizumab vs 7 patients (7.0%) receiving placebo achieved sPGA 0/1 scores (placebo-adjusted differences: PASI 90: 70.8%; 95% CI, 65.7%-76.0%; sPGA 0/1: 76.5%; 95% CI, 70.4%-82.5%; P < .001 for both). At week 28, 336 responders were rerandomized to risankizumab (n = 111) or treatment withdrawal (n = 225). At week 52, the sPGA 0/1 score was achieved by 97 patients (87.4%) receiving risankizumab vs 138 patients (61.3%) receiving placebo. At week 104, the sPGA 0/1 score was achieved by 90 patients (81.1%) receiving risankizumab vs 16 patients (7.1%) receiving placebo (placebo-adjusted differences: week 52: 25.9%; 95% CI, 17.3%-34.6%; week 104: 73.9%; 95% CI, 66.0%-81.9%; P < .001 for both). Rates of treatment-emergent adverse events were similar between risankizumab (186 [45.7%]) and placebo (49 [49.0%]) in part A1 and remained stable over time. Risankizumab showed superior efficacy compared with placebo through 16 weeks and treatment withdrawal through 2 years. Risankizumab was well tolerated, with no unexpected safety findings during the 2-year trial. ClinicalTrials.gov Identifier: NCT02672852.

The Johannine Footwashing as the Sign for Perfect Love: An Exegetical Study of John 13:1–20

Originally presented as a doctoral dissertation to the Katholieke Universiteit, Leuven, Mathew’s study is an analysis of John 13:1–20. Following a brief introduction, she reviews the previous literature. The discussion of John 13:1–20 falls into two categories. Scholars such as Culpepper and Thompson conclude that the footwashing scene is non-sacramental, for the pericope develops theological themes found elsewhere in John. Others, such as Moloney and Thomas, interpret the passage sacramentally, perhaps reflecting the practice of the Johannine community itself.In ch. 2, Mathew provides a text-critical analysis of John 13:1–20. She gives particular attention to the long and short readings of 13:10. Mathew concludes that the longer reading, where Jesus announces that the one who has bathed (λελουμένος) need only wash (νίψασθαι) their feet, is most likely the authentic reading. The former term refers to receiving Jesus’s words, whereas the latter refers to physical washing; in 13:10, to washing one’s feet before a meal. Thus, νίψασθαι contains no reference to purification. A sacramental interpretation of John 13:1–20 is excluded.Chapter 3 contextualizes John 13:1–20 in light of biblical, ancient Near Eastern, and Greco-Roman literature. Footwashing was often performed before meals. Providing water for guests to wash their own feet was considered an important act of hospitality (Luke 7:44). In Exod 30:10–21, footwashing also featured as an element of ritual purity. In these instances, however, water was provided so individuals could wash their own feet. On certain occasions, servants washed the feet of guests, or a person of inferior social status washed the feet of an individual of higher status. There are no parallels to a teacher washing disciples’ feet during a meal.John 13:1–20 also has a specific literary purpose. This function is explored on macro and micro levels in chs. 4–5. The role of the footwashing scene as the introduction to John 13–17 is discussed in ch. 4. Mathew rejects source theories that separate all or part of 13:1–20 from 13:1–38. John 13:1–38 serves as an introduction to the final discourse in John 14–17. While possessing superficial similarities to departure narratives in Greco-Roman accounts of symposia, there are also significant differences between John 14–17 and accounts of symposia. The explanation is that John “bends” the symposium genre in service of his Christology.In ch. 5, Mathew proposes that John 13:1–20 is structured chiastically. Part A (13:1) is understood as describing Jesus’s identity and mission. The corresponding Part A1 (13:20) indicates the identity and mission of Jesus’s “own,” the disciples. Part B (13:2) is described as love denied, where Satan has placed into Judas’s heart the plan to betray Jesus. In conjunction, Part B1 (13:18–19) is understood as affirming love, where the Johannine Jesus expresses his love for all the disciples, despite Judas’s transgression of sacred table fellowship (Ps 41:10 as quoted in John 13:18). Part C (13:3) notes Jesus’s authority. Part C1 (13:16–17) describes the authority of those sent as Jesus’s agents in language reminiscent of Jesus’s own authority. Part D (13:4–11) describes Jesus’s act of life-giving love. In Part D1 (13:12–15) those at the meal are commanded to demonstrate the same love toward one another. The chapter concludes with a discussion of the impact of the language of the Synoptic Gospels on John’s presentation of Jesus’s words (pp. 218–29).Chapters 6–9 provide detailed exegesis of the chiasm. Particularly interesting is Mathew’s translation of the phrase “he loved them to the end” in 13:1 as “he loved them perfectly.” Jesus, who has knowledge of all things (3:3) provides an example of perfect love in the act of footwashing. In the same authority and humility, the disciples of the Johannine Jesus are sent on their mission (13:16–17). However, the recipients of Jesus’s love were all deeply flawed. They included the betrayer, Judas, the denier, Peter, and the remaining disciples who would desert Jesus in his hour of need. In light of these observations Mathew concludes that the Johannine love ideal is not restricted to the community but also extends to outside opponents. John 13:1–20 is, in short, an acted parable of the Synoptic command to love one’s enemies.Mathew advances our understanding of the footwashing scene of John 13. Whether her conclusions that 13:1 refers to Jesus’s perfect love, and that this love is inclusive, will need further investigation. Her observations do challenge those who conclude that the Johannine love ethic is exclusive of those outside the community. Perhaps John 13:1–20 provides a commentary on the tradition reflected in Matt 5:44–48. If so, scholars will need to continue their consideration of the relationship between John and the Synoptic or pre-Synoptic tradition.

Surgical Treatment and Rehabilitation of Trigger Thumb and Finger

The aim of the study was to evaluate the results of surgical treatment and rehabilitation of patients with trigger thumb and finger. In 40 patients, comprising 30 women and 10 men aged 26 to 64, a total of 42 cases of trigger thumb and finger. In the preoperative period, the severity of changes were studied according to the classification developed by Newport et al. Five patients were classified in the first stage, 28 in the second, 6 in the third, and 1 in the fourth. The mean duration of symptoms was five months. The indication for surgery was a lack of improvement following conservative treatment. All of the patients were treated surgically using the open method by cutting the flexor tendon sheath in part A1. The rehabilitation treatment included exercises to improve the range of mobility of the thumb and fingers and to stretch, grelax, and strengthen muscles. Neuromobilisation and automobilisation exercises were conducted. After 5 months, swelling, pain and restricted mobility of the thumb and fingers subsided in all patients. There were no ‘jumping’ symptoms. Apart from a slight transitory inflammatory reaction in 2 patients there were no complications. In patients with trigger finger, open surgery and competent rehabilitation therapy enables the achievement of very good results, with a low complication rate.

Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study

Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m(2) per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770. 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10.1 years (range 1.1-21.4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m(2) twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted. Pfizer and National Cancer Institute grant to the Children's Oncology Group.

Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology Group phase I consortium study.

9500 Background: Genetic aberrations in the anaplastic lymphoma kinase (ALK) gene are found in anaplastic large cell lymphoma (ALCL), neuroblastoma (NB) and other tumors.Crizotinib,a small molecule inhibitor of ALK and c-Met, is active in non-small cell lung cancers (NSCLC) harboring an ALK translocation. We performed a phase 1 dose-escalation and pharmacokinetic (PK) trial of crizotinib in patients (pts) with refractory solid tumors and ALCL. Methods: Crizotinib was administered bid without interruption in 28 day cycles using the rolling-six design. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2/dose) have been evaluated (A1). Pts with confirmed ALK fusion proteins, mutations or amplification (A2) could enroll at one dose level lower than part A1 and those with NB could enroll on a separate stratum (A3). PK studies were performed on day 1 and at steady state (SS). ALK genomic status in tumor tissue was evaluated and qPCR was used to measure NPM-ALK fusion transcript in bone marrow and blood samples of ALCL pts. Results: 70 pts were enrolled, 57 fully evaluable for toxicity, [median (range) age 9.9 yrs (1.1–21.3)]: 29 on A1, 18 on A2, and 10 on A3. In A1, 2/7 pts developed DLT (grade 3 dizziness, grade 5 intra-tumoral hemorrhage) at 215 mg/m2 and 1/6 pts developed DLT (grade 4 liver enzyme elevation) at 365 mg/m2. In A2, 1 grade 4 DLT (neutropenia) occurred at 165 mg/m2; in A3, no DLTs occurred. Mean (±SD) Cave (=AUC0-12h/12h) of crizotinib at SS was 466±114 ng/mL at 215 mg/m2/dose (n=5), 443±121 ng/mL at 280 mg/m2/dose (n=8), and 720±230 ng/mL at 365mg/m2/dose (n=4). Response data for pts with ALCL (six at 165 mg/m2, two at 280 mg/m2) approved for release by the Data Safety Monitoring Committee demonstrates 7/8 (88%) complete response (CR) rate to date. RT-PCR data for 6 of these pts at 57 time points was obtained and will be described. In addition, 2 pts with NB have had CRs, one with a documented ALK mutation. One patient with an inflammatory myofibroblastic tumor and one with NSCLC had PRs. Conclusions: Inhibition of ALK in pediatric pts with ALK-driven tumors occurs with minimal toxicity and is associated with objective anti-tumor activity.