bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1b study to evaluate safety, tolerability, pharmacokinetics, and efficacy of SER-155 in adults undergoing hematopoietic stem cell transplantation to reduce the risk of infection and graft versus host disease (NCT04995653).
Authors: Ponce Doris M. , Lombardo Mary-Jane , Ford Christopher B. , Peled Jonathan U. , Van Den Brink Marcel R. M. , Tejura Bindu 
Published: June 2022

TPS7074 Background:In patients undergoing allogeneic hematopoietic stem cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is a cultivated investigational microbiome therapeutic rationally designed to improve clinical outcomes in patients undergoing HCT by restoring colonization resistance to pathobionts, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study to evaluate the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT. Methods:This study will enroll approximately 70 subjects ≥ 18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo and stratified by conditioning regimen intensity. Exclusion criteria include history of severe colitis of any etiology or active inflammatory bowel disease or total colectomy, transplant using umbilical cord blood or ex vivo T-cell therapy, receipt of fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, subjects in both cohorts will receive 2 treatment courses (before and after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, and a conditional 3rd treatment course if the subject receives antibiotics (Table). Safety outcomes will be followed through 52 weeks post HCT. The primary endpoint is to evaluate the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival in placebo vs SER-155 arms. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. Clinical trial information: NCT04995653. [Table: see text]
KITE-363: A phase 1 study of an autologous anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) B-cell lymphoma (BCL).
Authors: Nastoupil Loretta J. , Dahiya Saurabh , Miklos David Bernard , Reagan Patrick Michael , Ulrickson Matthew , Jung A. Scott , Kloos Ioana , Dong Jinghui , Chou Justin , Murakami Jodi , Rodriguez Katherine , Nahas Myrna 
Published: June 2022

TPS7579 Background: One mechanism by which B-cell tumors can resist the effects of CD19-targeted CAR T-cell therapy is through CD19 antigen escape (Neelapu et al. ASH 2019). Recent analyses in large B-cell lymphoma (LBCL) demonstrated that approximately one-third to two-thirds of relapses after infusion of CAR T-cell therapy were CD19 negative (Plaks et al. Blood. 2021; Spiegel, Dahiya et al. Blood. 2021; Spiegel et al. Nat Med. 2021). KITE-363 is an autologous CAR T cell transduced with a bicistronic vector with resultant expression of a CD19 CAR with a CD28 costimulatory domain and a CD20 CAR with a 41BB costimulatory domain. In preclinical studies, KITE-363 recognized and eliminated tumor cells expressing CD19 and/or CD20. KITE-363 CAR T-cell therapy has the potential to rescue CD19-negative relapsing patients with BCL as well as prevent CD19 antigen escape by minimizing selective pressure through upfront therapeutic dual targeting. This Phase 1, first-in-human, open-label, multicenter study (NCT04989803) will evaluate the safety and preliminary efficacy of KITE-363 in patients with R/R BCL. Methods: The Phase 1 design includes a 3+3 dose-escalation portion (1A), with 5 planned CAR T-cell levels, and a dose expansion portion (1B). Patients may receive optional corticosteroid bridging therapy following leukapheresis. Patients will then receive conditioning chemotherapy (cyclophosphamide and fludarabine) on Day ‒5 to Day ‒3 followed by KITE-363 infusion on Day 0. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per Lugano criteria (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete response rate, time to next treatment, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells in blood and cytokines in serum. Eligible adult patients have histologically confirmed BCL, including LBCL, indolent non-Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma (HL), and BCL, unclassifiable (with features intermediate between diffuse LBCL and classical HL), that is R/R after ≥2 lines of therapy (patients with LBCL may have primary refractory disease). Other key inclusion criteria are adequate bone marrow and organ function and ECOG performance status 0‒1. Key exclusion criteria are central nervous system (CNS) involvement from lymphoma, active infection including hepatitis B and C, and clinically significant CNS disorder. This study is currently open and accruing patients. Clinical trial information: NCT04989803.
A phase 1/2 study of BLU-945 in patients with common activating EGFR-mutant non–small cell lung cancer (NSCLC): SYMPHONY trial in progress.
Authors: Shum Elaine , Elamin Yasir Y , Piotrowska Zofia , Spigel David R , Reckamp Karen L. , Rotow Julia K , Tan Daniel Shao-Weng , Lim Sun Min , Kim Tae Min , Lin Chia-Chi , Kato Terufumi , Parepally Jagan , Albayya Faris , Louie-Gao Melinda , Weinig Tessa , Zalutskaya Alena , Goto Koichi 
Published: June 2022

TPS9156 Background: Although EGFR-targeted therapies have improved outcomes in patients with EGFR-mutant ( EGFRm) NSCLC, such as EGFR ex19del and L858R, resistance to these drugs is inevitable. BLU-945 is an investigational next-generation EGFR tyrosine kinase inhibitor (TKI) designed to suppress common activating and on-target resistance EGFR mutations, such as C797S and T790M. Preclinically it has shown activity as monotherapy in osimertinib-resistant patient-derived xenograft (PDX) models. In addition, BLU-945 has > 450-fold selectivity for C797S and T790M mutants over wildtype, advantageous for combinations with complementary EGFR-targeting agents, such as osimertinib. These combinations have shown enhanced activity in PDX models. The SYMPHONY trial (BLU-945-1101; NCT04862780) is an international, open-label, first-in-human, phase 1/2 study designed to evaluate safety, tolerability, and antitumor activity of BLU-945 as monotherapy and in combination with osimertinib in patients with EGFRm NSCLC. Methods: Key eligibility criteria include adults with pathologically confirmed metastatic NSCLC with an activating EGFR mutation, Eastern Cooperative Oncology Group performance status 0–1, and previous treatment with ≥1 EGFR-targeted TKI. Patients with asymptomatic brain metastases who are on stable doses of corticosteroids are eligible. Tumors with additional known driver alterations, including EGFR exon 20 insertions and other kinase drivers, are excluded. Primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D) and safety (phase 1); and overall response rate (ORR) by RECIST 1.1 (phase 2). Key secondary endpoints include ORR, duration of response (DOR), pharmacokinetics (PK), and pharmacodynamics (PD; phase 1); and DOR, progression-free survival, overall survival, CNS efficacy, PK, and safety (phase 2). Phase 1 dose escalation will be done using Bayesian optimal interval design; ̃85 patients will receive BLU-945 monotherapy and ̃18 will receive combination BLU-945 and osimertinib. In the phase 2 dose expansion, patients will receive BLU-945 at the RP2D of the monotherapy in 3 groups based on EGFR mutational profile: T790M and C797S (n≈37), T790M, but not C797S (n≈12), and C797S, but not T790M (n≈12). In a combination group, BLU-945 plus osimertinib will be administered at RP2D of the combination to n≈24 patients, ≥12 with both T790M and C797S mutations. Patients may receive treatment until disease progression or unacceptable toxicity. Recruitment has started and approximately 30 sites will be open for enrollment across North America, Europe, and Asia. Clinical trial information: NCT04862780.
Randomized phase 2 study evaluating efficacy and safety of inupadenant in combination with chemotherapy in adults with metastatic non–small cell lung cancer (mNSCLC) who progressed on immunotherapy.
Authors: O'Brien Mary E.R. , Cheema Parneet K. , Grohé Christian , Costa Enric Carcereny , Girard Nicolas , Chiappori Alberto , Ross Sally , Rossetti Maura , Dubois Frederic , Lager Joanne J. , Srivastava Shouryadeep , Velcheti Vamsidhar 
Published: June 2022

TPS9158 Background: In cancer, the accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression mainly via the high affinity A2A receptor (A2AR), causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. This results in increased tumor cell survival and immune escape (Blay 1997; Merighi 2003; Muller-Haegele 2014). Therefore, inhibiting A2AR could reverse immunosuppression and re-establish immune surveillance in the tumor microenvironment. Inupadenant is an antagonist of the A2AR with potent inhibition of A2AR even at the high concentrations of adenosine present in the tumor microenvironment. Ongoing clinical studies have established inupadenant as a molecule with a favorable safety profile with preliminary evidence of clinical activity in multiple tumor types, including durable PRs in patients who have exhausted standard treatment options (Buisseret 2021). The standard treatment for patients without a driving mutation who progress on first-line IO is a platinum-based doublet chemotherapy regimen. Carboplatin plus Pemetrexed (C+P) is the preferred chemotherapy in nonsquamous mNSCLC. Study A2A-005 will evaluate the efficacy of inupadenant in combination with C+P as a second-line therapy in adult patients with nonsquamous mNSCLC (post-IO). A successful outcome from study A2A-005 will help address a high unmet need for this patient population and could lead to new therapeutic options. Methods: This is a 2-part study. The first part is an open label dose-finding part to determine the safety and recommended Phase 2 dose (RP2D) of inupadenant in combination with C+P (N = 40). In Part 2, 150 patients will be randomized 1:1 to inupadenant or placebo, both in combination with C+P. Tumor response will be determined according to RECIST 1.1 criteria and safety findings will be reviewed by the Safety Review Committee (for Part 1) and the Data Monitoring Committee (for Part 2). Key eligibility criteria include 1) mNSCLC of nonsquamous pathology, 2) have received only 1 line of anti-PD-(L)1 therapy in the metastatic setting, without concomitant chemotherapy, and have progressed (IO/IO combination therapy is allowed), 3) have measurable disease as defined by RECIST v1.1 criteria and 4) Eastern Cooperative Oncology Group status ≤1. Primary endpoints are RP2D (for Part 1) and PFS (for Part 2). Secondary endpoints include change in tumor size, ORR, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. The study will be conducted in approximately 11 countries in North America and Europe. Clinical trial information: EudraCT 2021-005487-22.
DETECTION phase II/III trial: Circulating tumor DNA–guided therapy for stage IIB/C melanoma after surgical resection.
Authors: Lee Rebecca , Rothwell Dominic G. , Jackson Richard , Smith Nigel , Wong Stephen Q , Kelso Noel , Burghel George , Hewitt Chelsee , Clarke Harry , Mitchell Jackie , Jones Kate , Muinonen-Martin Andrew , Turajlic Samra , Corrie Philippa Gail , Marais Richard , Middleton Mark R. , Dawson Sarah-Jane , Sandhu Shahneen , Dive Caroline , Lorigan Paul 
Published: June 2022

TPS9603 Background: Circulating tumor DNA (ctDNA; the tumor derived fraction of circulating free DNA in the blood) is a well recognized, minimally-invasive biomarker of tumor burden/progression in many cancers. We have previously shown in retrospective and prospective cohorts of patients with melanoma that ctDNA analysis of serial blood samples following curative intent surgery can identify minimal residual disease (MRD) or molecular relapse. The majority of patients with resected stage II melanoma do not recur, therefore better strategies to identify high risk patients are required. Furthermore, a consistent finding in studies of immune therapy in stage IV melanoma is that patients with small volume disease have the best outcome. We aim to test whether early relapse can be identified by ctDNA analysis and acted upon in a clinically relevant timeframe, and if early treatment of molecular recurrence with immune therapy improves outcomes for patients with resected stage IIB/C melanoma. Methods: We designed a phase II/III multicenter study across 21 UK and 4 Australian sites with a tumor informed approach employed for ctDNA detection. Droplet digital assays for BRAF/NRAS/TERT promoter mutations were validated for sensitive ctDNA detection across two accredited clinical testing laboratories. Patients with stage IIB/C melanoma, BRAF/NRAS/TERT promoter mutant cutaneous melanoma, ECOG 0/1, adequate organ function, with complete resection (including sentinel lymph node biopsy) performed within 12 weeks and radiological/clinical disease-free status confirmed within 4 weeks prior to registration, no prior immune/targeted therapy will be followed up with blinded ctDNA sampling in addition to clinical follow-up. Patients with ctDNA detected will be randomised 1:1 in a double blind fashion to continue routine follow-up with investigators choice treatment if they develop disease recurrence, or unblinded and treated with nivolumab 480mg IV Q4-weekly. Primary objectives include i) whether MRD/molecular relapse following curative intent surgery can be identified earlier than clinical relapse, ii) whether early treatment of molecular recurrence with nivolumab improves overall survival. 1050 patients are planned to be enrolled. The study opened in the UK in November 2021 and will open in Australia in Spring 2022. Clinical trial information: NCT04901988.
Capturing uveal melanoma (UM) global practice patterns and clinical outcomes in the collaborative ocular melanoma natural history (OMNi) study (NCT04588662).
Authors: Sacco Joseph J. , Orloff Marlana M. , Patel Sapna Pradyuman , Conway Max , Lim Li-Anne , Fog Lotte S. , Sia David , McKenzie John , McKay Daniel , O'day Roderick , Isaacs Timothy , Shoushtari Alexander Noor , Sullivan Ryan J. , Kin Sarah , Gwadry-Sridhar Femida Hussein , Joshua Anthony M. , Carvajal Richard D. 
Published: June 2022

TPS9610 Background: Geographical differences in the management of primary UM, surveillance for recurrence, and care of metastatic disease have emerged based upon local expertise, treatment availability and insurance coverage. We have initiated accrual to OMNi (NCT04588662), an ambispective database developed to provide contemporary real-world data of UM, capturing its natural history and serving as a virtual biospecimen repository. The overall objectives of OMNi are to characterize regional/international UM management practice patterns and associated clinical outcomes in an effort to inform best practice recommendations. Methods: OMNi utilizes the Pulse Infoframe Healthie platform, a globally compliant platform which enables the structured collection of data mapped to Observational Medical Outcomes Partnership. The data fields created permit longitudinal capture of data including baseline patient and tumor characteristics, treatment of primary lesion and outcomes, surveillance patterns, time to disease recurrence, treatment of recurrent disease with outcomes, and survival. Inclusion criteria include a diagnosis of uveal melanoma and the ability to provide written informed consent for participation in the prospective registry or an institutional waiver by the IRB/ethics committee for retrospective data collection without written informed consent. We have initiated data collection at 3 US and 3 Australian centers, with 184 patients enrolled to date. Based upon feasibility assessment, we anticipate retrospective data entry for ̃2,000 patients and annual recruitment of ̃700 patients once all centers are active. Data collected in this OMNi collaboration, which will include additional US, UK and Australian sites, will facilitate new insights, hypothesis testing, as well as clinical trial development and conduct, and through a governance structure, will be made accessible for research. The OMNi dataset can serve and aid in interpretation of clinical trial outcomes in the real-world, facilitate cutting-edge research, and accelerate the development of diagnostics and therapeutics. Clinical trial information: NCT04588662.
Pharmacological effect of Lidang Tang against adjuvant-induced rheumatoid arthritis in rats
Authors: Liu Na , Lei Tao , Liu Xifang , Dong Bo , Zeng Xueqin , Sun Yindi 
Published: June 2022

Rheumatoid arthritis (RA) is a great concern across the globe. It is characterized as an autoimmune disease, where the body's immune system mistakenly attacks bone joints causing them to erode which leads to deformity in structure. Thus, the present study was conducted to elucidate the effect of Lidang Tang (LDT) decoction, a traditional Chinese medicine against rheumatoid arthritis. The rheumatoid arthritis was induced in Sprague-Dawley albino rats by intradermal injection of bovine collagen II type at the tail. Results suggested that LDT reduces paw swelling and arthritic scores in rats. The protective effect of LDT against RA was further substantiated by histopathological analysis of synovial tissue of rats, where LDT improves the architecture of the tissues as compared to CIA rats. It also reduces oxidative stress and inflammation in CIA rats as compared to the disease model group. The serum level of anti-collagen II-specific immunoglobulins (IgG1 and IgG2a) was reduced significantly in LDT treated group. In a western blot analysis, LDT treated group showed a significant reduction in the expression of NF-ĸB and COX-2 as compared to CIA rats. Collectively, our study for the first time demonstrated the protective effect of Lidang Tang decoction against rheumatoid arthritis.
Effect of zinc supplementation during cryopreservation on post-thaw chicken semen parameters and fertility
Authors: Murugesan Shanmugam , Mahapatra Ramkrishna 
Published: June 2022

The present study evaluated supplementation of zinc from different sources during chicken semen cryopreservation on post-thaw semen quality and fertility. Adult White Leghorn chicken semen was cryopreserved using 4% dimethyl sulfoxide (DMSO) in Sasaki diluent (SD). In the semen cryomixture zinc oxide (6.25 and 12.5 µM) and zinc sulphate (100 and 200 µM) was added and cryopreserved. The plastic semen straws were thawed at 5°C for 100 sec and samples were evaluated for sperm motility, live, abnormal and acrosome intact sperm. The lipid peroxidation in the seminal plasma was evaluated. The semen cryopreservation and evaluation were repeated on six occasions. Fertility of the zinc supplemented semen was evaluated by inseminating into White Leghorn hens. Zinc supplementation did not affect any of the post-thaw sperm parameters. The lipid peroxidation and fertility were similar between the treatments. In conclusion, supplementation of zinc as zinc oxide or zinc sulphate during chicken semen cryopreservation does not affect post-thaw semen parameters or fertility.
Optimization of the structure of bionic finger segment prosthesis using generative design
Authors: Triono Agus , Darsin Mahros , Fathurrahman Arsi , Mulyadi Santoso , Ilminnafik Nasrul 
Published: June 2022

Background: Bionic hand prosthesis helps restore the original hand function. A survey on prosthetic users concluded that 79% thought that their devices were "too heavy". Therefore, the weight of the prosthesis is a major cause of user discomfort and fatigue. This research was aimed at the reduction of hand mass bionic prosthesis by optimizing the structure of the fingers with generative design methods. Methods: The materials used were Acrylonitrile butadiene styrene plastic and Nylon 6, and the manufacturing method used Additive Manufacturing. The prosthesis was designed with a lighter finger structure with a max displacement of 2 mm and a maximum safety factor of 4. Results: Generative design produced more than 80 designs. The selection of the best design was based on the status of design solutions, research limitations, visual aesthetics, recommendation values, and validation of mechanical performances. The best is the SS-2. This design has an 80% lighter mass with the highest safety factor of 3.79, the lowest stress of 5.26 MPa, and the maximum displacement of 0.61 mm. Conclusion: Based on the exploration scheme, the generative design could produce more than 80 design solutions. The selection of the best design was based on the status of design solutions, research limitations, visual aesthetics, recommendation values, and validation of mechanical performances in the design. Design validation was carried out by simulating finite element analysis with static stress study methods in selected design candidates with input study cases similar to generative design exploration schemes. Finally, SS – 2 design was the best design produced by the generative design method with the highest factor of safety value of 3.79. Also gives an advantage to a stress value of at least 5.26 MPa in cases of segment loading, as well as the maximum displacement value of 0.61 mm.