bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II/III study of JZP-458 in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who are hypersensitive to E. coli-derived asparaginases.
Authors: Maese Luke , Rau Rachel E. , Raetz Elizabeth A. , Lin Tong , Kim Pil , Chandula Reddy , McClung Sherrie , Gray Julie , Choi L. Mi Rim , Loh Mignon L. , Adamson Peter C. 
Published: May 2020

TPS7568 Background: L-asparaginase is an important component of ALL therapy and the inability to receive asparaginase secondary to hypersensitivity has been associated with poor patient (pt) outcomes. Alternative options for pts after hypersensitivity reactions are needed. JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross-reactivity to E. coli–derived asparaginases. In a phase 1 study, JZP-458 was well tolerated and maintained adequate (≥0.1 IU/mL) serum asparaginase activity (SAA), a surrogate marker for asparagine depletion, for up to 72 hrs in healthy adults. Methods: This is a pivotal, open-label, multicenter, dose confirmation, and pharmacokinetic (PK) study (NCT04145531) of JZP-458 in pts with ALL/LBL who develop hypersensitivity reactions to a long-acting E. coli–derived asparaginase and have ≥1 course of asparaginase remaining in their treatment plan (Table); 6 doses of JZP-458 will be substituted for each remaining course. Treatment duration will depend on the number of asparaginase courses remaining in the treatment plan. The study has 2 sequential parts: Part A will determine the dose of intramuscular (IM) JZP-458 and confirm safety/efficacy; Part B will explore the dose/schedule of intravenous (IV) JZP-458. Blood samples will be collected to determine SAA levels and pts will be monitored for adverse events. Immunogenicity of JZP-458 will be assessed. Primary objectives are to determine (1) the efficacy of IM JZP-458 measured by the last 72-hr nadir SAA (NSAA) level (≥0.1 IU/mL) during the first treatment course, and (2) the safety/tolerability of IM JZP-458. Secondary objectives are to determine the efficacy (measured by the last 48-hr NSAA level [≥0.1 IU/mL] and the last 48- and 72-hr NSAA levels [≥0.4 IU/mL]), PK, and immunogenicity of IM JZP-458. Exploratory objectives include efficacy, safety, PK, and immunogenicity of IV JZP-458. The trial is active and enrolling. Clinical trial information: NCT04145531 . [Table: see text]
Trial in progress: a phase II, multicenter, single-arm study of zanubrutinib (BGB-3111) in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma intolerant of prior treatment with ibrutinib.
Authors: Flinn Ian , Shadman Mazyar , Freeman Benjamin Bruce , Chen Dih-Yih , Zhang Xiaoping , Cohen Aileen , Ro Sunhee K. , Huang Jane , Sharman Jeff P. 
Published: May 2020

TPS8066 Background: Ibrutinib (ibr), a Bruton tyrosine kinase inhibitor (BTKi), was shown to improve patient outcomes in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for discontinuing ibr (50% and 63% of discontinuations in relapse/refractory (R/R) and frontline patients, respectively; Haematologica. 2018:103:874). Zanubrutinib, an approved BTKi for mantle cell lymphoma, was specifically engineered to optimize selectivity. Pooled clinical data from 6 zanubrutinib monotherapy trials in B-cell malignancies (N=682 patients; R/R CLL/SLL [n=91]) suggested that zanubrutinib monotherapy was well tolerated and demonstrated a low rate of treatment discontinuation from AEs (9%; Tam, EHA 2019). Presented here is a trial-in-progress that will evaluate whether zanubrutinib monotherapy may serve as a therapeutic option for patients with CLL/SLL who have become ibr intolerant. Methods: The ongoing phase II, multicenter, US, single-arm, open-label study (NCT04116437, BGB-3111-215) will evaluate zanubrutinib monotherapy (160mg twice daily) as a treatment option for patients with CLL/SLL intolerant to prior ibr treatment. Approximately 60 patients will be enrolled from ~30 community medical centers. Key inclusion criteria include CLL/SLL requiring treatment per International Workshop on CLL criteria ( Blood. 2018;131:2745) before ibr therapy, intolerance to ibr (defined as an unacceptable AE for which, per investigator’s opinion, ibr treatment should be discontinued despite optimal supportive therapy), resolution of ibr-related AEs to grade ≤1 or baseline, and an ECOG PS 0-2. Key exclusion criteria include having an intervening cancer therapy between ibr and zanubrutinib, a documented disease progression during ibr treatment up to the time of enrollment, and a history of central nervous system (CNS) hemorrhage. The primary endpoint is frequency and severity of protocol-specified treatment-emergent AEs (diarrhea, myalgia, muscle spasm, arthralgia, hypertension, fatigue, rash, atrial fibrillation, and hemorrhage excluding CNS hemorrhage). The secondary endpoints include overall response rate, progression-free survival, and patient-reported outcomes. An exploratory endpoint was added to evaluate clinical effects (physical activity, treatment-related symptoms, and quality of life) using a smartphone app. Recruitment is ongoing. Clinical trial information: NCT04116437 .
An intergroup collaboration for advanced stage classical Hodgkin lymphoma (cHL) in adolescents and young adults (AYA): SWOG S1826.
Authors: Castellino Sharon M. , LeBlanc Michael Leo , Herrera Alex Francisco , Parsons Susan K. , Punnett Angela , Hodgson David C. , Rutherford Sarah C. , Khan Nadia , Constine Louis S. , Davison Kelly , Prica Anca A. , Friedberg Jonathan W. , Kelly Kara M. 
Published: May 2020

TPS8067 Background: Treatment for pediatric cHL varies considerably from that in adult cHL. Hence there are gaps in risk prediction and optimal therapy for de-novo advanced stage disease across the adolescent and young adult (AYA) age spectrum. Early access to novel agents for AYA could be facilitated via collaboration with adult research groups through the U.S. National Cancer Institute’s National Clinical Trials Network (NCTN). The PD-1 inhibitor Nivolumab (Nivo) has safety and efficacy in relapsed and refractory disease in children and adults, but has not been evaluated in de-novo disease to date. Methods: North American cooperative group lymphoma chairs, Cancer Therapy Evaluation Program (CTEP) representatives and patient advocates met to establish consensus on the comparison arms and study design, based on recent historical approaches across adult and pediatric groups. Study champions were identified across North American cooperative groups and include expertise in imaging, radiation oncology, biology and patient-reported outcomes. A therapeutic study was designed with the primary aim being to compare progression-free survival with novel targeted agents in advanced stage cHL. S1826 (NCT03907488), led by SWOG Cancer Research Network, opened to accrual in July 2019. Eligibility criteria include age > 12 years, and Stage III or IV cHL. Patients are randomized (1:1) to 6 cycles of either Nivo-Adriamycin, Vinblastine, Dacarbazine (AVD) or Brentuximab vedotin (Bv)-AVD. Enrollment is stratified by age, baseline International Prognostic Score, and provider intent to use involved site radiation therapy (ISRT). Protocol-prescribed ISRT is response-adapted, based on end of therapy imaging. The primary endpoint is a comparison of progression-free survival between arms. Secondary clinical endpoints include comparison of: overall survival, metabolic response at the end of therapy, physician-reported adverse events, patient-reported adverse events, and health-related quality of life (overall, and specific to fatigue and neuropathy). This unique intergroup collaboration demonstrates the process and the feasibility of consensus study designs toward early adoption of targeted therapies and harmonization of treatment approaches for AYA populations. Clinical trial information: NCT03907488 .
A phase II study of MT-3724, a novel CD20-targeting engineered toxin body, to evaluate safety, pharmacodynamics, and efficacy in subjects with relapsed or refractory diffuse large B-cell lymphoma.
Authors: Diaz Duque Adolfo Enrique , Perekhrestenko Tetiana , Musteata Vasile , Zodelava Mamia , Guthrie Troy H. , Strack Thomas , Burnett Christine , Wilson Sarah , Waltzman Roger J. , Baetz Tara D. , Persky Daniel O. 
Published: May 2020

TPS8074 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A. It is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). Methods: The primary objective of this single-arm, Phase 2 study (NCT02361346) is to determine the efficacy of MT-3724 monotherapy in r/rDLBCL based on overall response rate (ORR), defined as the proportion of subjects with a complete/partial response according to the Lugano criteria, as assessed by independent, central review. Key secondary objectives include safety, progression-free survival, investigator‐assessed ORR, duration of response, overall survival, and pharmacodynamics. Adverse events will be assessed and documented according to Common Terminology Criteria for Adverse Events version 5.0. Key eligibility criteria include adult subjects with histologically confirmed, r/rDLBCL, with ≥2 prior standard of care systemic NHL treatment regimens, and ≥1 measurable lesion. As rituximab and other CD20-targeting antibodies compete with MT-3724 for the same CD20 domain, minimum washout periods from these agents must be observed. Subjects remain eligible post stem cell transplant or chimeric antigen receptor T-cell therapy. Subjects will receive 50 µg/kg MT-3724 IV over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. The anticipated sample size is N = 100. Interim analyses will be performed to confirm minimum efficacy thresholds based on the encouraging data observed in the completed phase 1 portion of the study [Hamlin et al. Blood 2019;134(Suppl 1):4098]. Multiple global sites are enrolling subjects. Clinical trial information: NCT02361346 .
Phase I study of radiotherapy (RT) & durvalumab in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) & follicular lymphoma (FL): The RADD study.
Authors: Hawkes Eliza Anne , Manos Kate , Chong Geoffrey , Palmer Jodie , MacManus Michael Patrick , Keane Colm , Scott Andrew Mark , Shortt Jake , Ritchie David , Churilov Leonid , Johnston Laura , Witkowski Tom , Barraclough Allison Anne , Lee Sze Ting , Lin Wendi , Koldej Rachel , Khor Richard 
Published: May 2020

TPS8075 Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. PD1/PDL1 inhibitors yield high response rates in some lymphomas, but single agent therapy in heavily pre-treated pts are disappointing. RT stimulates anti-tumor immunity through several mechanisms and may enhance response to immune checkpoint inhibition (ICI). Concurrent ICI & RT is synergistic in preclinical studies & solid tumors, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumor antigen release and overcome clonal variation between disease sites to further augment the immune response. Methods: RaDD (NCT03610061) is a phase I, 3+3 dose escalation study to determine the safety profile of escalating dose & number of sites of RT in combination with Durvalumab (anti-PD-L1 antibody) in RR DLBCL & FL. Eligible pts (i.e. ≥1 prior therapy, ineligible for auto-SCT, no contraindication to PDL1i) receive 5 fractions of external beam RT to target site(s). 5 RT dose & site levels are included (dose range 2.5Gy-20Gy to 1-3 sites). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until confirmed disease progression. The DLT period is 28 days from start of RT. Primary endpoint is the recommended phase two dose (RP2D) of RT in combination with durvalumab. Secondary endpoints include response rates, PFS & OS. Correlative studies will examine the tumour-immune system interaction; an exploratory PET substudy with novel tracers for durvalumab (89Zr-Durvalumab) & CD8+ T cells (89Zr -Df-IAB22M2C) will also be performed. Projected enrollment for determination of maximum tolerated dose (MTD) & RP2D is 6-30 pts pending toxicity. Recruitment will continue to 36 pts for secondary endpoint analysis. 9 pts are enrolled across cohorts 1-3 to date. Clinical trial information: NCT03610061 .
Trial in progress: Neoadjuvant immune checkpoint blockade in resectable malignant pleural mesothelioma.
Authors: Reuss Joshua E. , Sepesi Boris , Rolfo Christian Diego , Zahurak Marianna , Anagnostou Valsamo , Smith Kellie Nicole , Cottrell Tricia , Stein Julie E. , Illei Peter Bela , Taube Janis M. , Rosner Gary L. , Murray Joseph Christopher , Nakajima Erica C. , Voong K Ranh , Hales Russell K. , Yang Stephen , Battafarano Richard James , Friedberg Joseph , Tsao Anne S. , Forde Patrick M. 
Published: May 2020

TPS9078 Background: While the role of surgery in limited-stage (stage I-III) malignant pleural mesothelioma (MPM) is controversial, many centers have adopted an aggressive tri-modality approach incorporating (neo)adjuvant chemotherapy, surgical resection and radiotherapy. Despite this, most patients relapse and die from their disease. Immune checkpoint blockade (ICB) has shown promise in advanced MPM, but the mechanisms of response and resistance remain elusive. Improving the mechanistic understanding of ICB in MPM while concurrently optimizing the treatment strategy for limited-stage MPM are two urgent unmet needs. This multicenter multi-arm phase I/II study seeks to evaluate the safety and feasibility of neoadjuvant ICB in resectable MPM, incorporating novel genomic and immunologic analyses to deliver mechanistic insight into the biology of ICB in MPM. Methods: Patients with surgically resectable stage I-III treatment-naïve epithelioid or biphasic MPM receive neoadjuvant treatment with nivolumab every 2 weeks for 3 doses with or without 1 dose of ipilimumab (arm A: nivolumab monotherapy; arm B: nivolumab + ipilimumab). After macroscopic complete resection, patients receive optional investigator-choice adjuvant chemotherapy +/- radiation. Following this, patients will receive up to 1 year of adjuvant nivolumab. Feasibility and safety are co-primary endpoints of this study with feasibility defined by a delay in surgery of ≤24 days from the preplanned surgical date and safety defined by adverse events according to CTCAE v5.0. Bayesian-designed stopping rules have been implemented for feasibility and safety. Secondary endpoints include assessment of pathologic response and radiographic response using RECIST 1.1 for MPM. Correlative analyses will be performed on tissue specimens obtained pre- and post-ICB, as well as blood obtained pre, during, and post-ICB. Key correlates include multiplex immunofluorescence and longitudinal ctDNA assessment. Whole exome sequencing, T-cell receptor sequencing, and the MANAFEST functional neoantigen assay will be utilized to identify neoantigen-specific T-cell clonotypes and track these clonotypes temporally (during/post ICB) and spatially (across immune compartments). Single-cell RNA sequencing will be used to characterize the functionality of expanded T-cell clonotypes. Accrual to arm B will commence following complete accrual to arm A with a planned total enrollment of 30 patients. This study is open with 1 patient enrolled at the time of submission. Clinical trial information: NCT03918252.
Randomized phase II study of canakinumab (CAN) or pembrolizumab (PEM) as monotherapy or in combination as neoadjuvant therapy in patients (Pts) with surgically resected (Stage IB-IIIA) non-small cell lung cancer (NSCLC): CANOPY-N.
Authors: Mok Tony S. K. , Garrido Lopez Pilar , Kim Edward S. , Arslan Cagatay , Pujol Jean-Louis , Song Yuanbo , Blin Cecile , Rodrik-Outmezguine Vanessa , Mookerjee Bijoyesh , Passos Vanessa Q. , Lee Jay M. 
Published: May 2020

TPS9626 Background: Complete surgical resection is the standard treatment (tx) for pts with stage I-IIIA NSCLC. 5-year survival rates range from 19-50%, with most pts dying from distant recurrence. Neoadjuvant or adjuvant chemotherapy improves overall survival (OS) by only 5% in pts with NSCLC, and new tx options are needed. Preliminary data with PD-1 or PD-L1 inhibitors as neoadjuvant therapy has shown major pathologic responses (MPR) or pathologic complete responses (pCR) in pts with early stage NSCLC. CANTOS study demonstrated reduced incidence of NSCLC and decreased lung cancer-related mortality with CAN (IL-1β inhibitor) versus placebo, in a dose-dependent manner for pts with atherosclerosis. In pre-clinical NSCLC humanized models, tx with CAN±anti PD-1 inhibitor could lead to anti-tumor activity. Combination of CAN and PEM is expected to enhance the efficacy of PD-1 inhibition by inhibiting dysregulated inflammation in tumor microenvironment. Based on available evidence, CANOPY-N study was designed to evaluate effect of CAN and PEM as monotherapy or in combination as neoadjuvant tx for pts with resectable NSCLC. Methods: CANOPY-N (NCT03968419) is a phase II, randomized, open-label study evaluating effect of CAN or PEM monotherapy or in combination as neoadjuvant tx in resectable NSCLC pts. Histologically confirmed stage IB-IIIA, tx-naive, ECOG PS 0-1 NSCLC pts eligible for surgery and with a planned surgical resection in approximately 4-6 weeks (after 1st dose of study tx), are eligible to participate. An archival (if obtained up to 6 months before 1st day of tx) or new biopsy is required. Approximately 110 pts will be randomized in 2:2:1 ratio (stratified by histology [squamous/non-squamous]) to one of the tx arms to receive a total of 2 doses (200 mg Q3w) of CAN alone (n = 44) or in combination with PEM (n = 44) or PEM (n = 22) with safety follow-up up to 130 days from last study drug dose. Primary endpoint is to determine MPR rate (≤10% of residual viable tumor cells at time of surgery), secondary endpoints include determination of ORR, MPR rate based on local review, surgical feasibility rates, anti-drug antibodies incidence and PK parameters. Clinical trial information: NCT03968419 .
Pulmonary Function in Patients With Multiple Endocrine Neoplasia 2B
Authors: Fuller Sarah , Del Rivero Jaydira , Venzon David , Ilanchezhian Maran , Allen Deborah , Folio Les , Ling Alexander , Widemann Brigitte , Fontana Joseph R , Glod John 
Published: May 2020

Abstract

Context
Multiple endocrine neoplasia type 2B (MEN2B) is a rare cancer predisposition syndrome resulting from an autosomal-dominant germline mutation of the RET proto-oncogene. No prior studies have investigated pulmonary function in patients with MEN2B.

Objective
This study characterized the pulmonary function of patients with MEN2B.

Design
This is a retrospective analysis of pulmonary function tests (PFTs) and chest imaging of patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B at the National Institutes of Health.

Results
Thirty-six patients with MEN2B (18 males, 18 females) were selected based on the availability of PFTs; 27 patients underwent at least 2 PFTs and imaging studies. Diffusion abnormalities were observed in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects. A declining trend in diffusion capacity was seen over time, with an estimated slope of −2.9% per year (P = 0.0001). Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36), respectively. Computed tomography imaging revealed pulmonary thin-walled cavities (lung cysts) in 28% (9/32) of patients and metastatic lung disease in 34% (11/32) of patients; patients with metastatic lung lesions also tended to have thin-walled cavities (P = 0.035).

Conclusions
This study characterized pulmonary function within a MEN2B cohort. Diffusion, restrictive, and obstructive abnormalities were evident, and lung cysts were present in 28% of patients. Further research is required to determine the mechanism of the atypical pulmonary features observed in this cohort.
Logistics Providers As Integrators of Intelligent Supply Chain Systems: an Innovative Aspect
Authors: Kamchatova E. 
Published: May 2020

This article is devoted to determining the role and place of logistics providers in managing international supply chains, analyzing their classifications and transforming business models in supply chains in the context of active e-Commerce development, as well as identifying specific features of system and virtual integrators of supply chains that can significantly increase the level of logistics service.
Active use of e-Commerce leads to a significant reduction in response times to demand and encourages supply chain managers to constantly search for new solutions and innovative technologies that enable companies involved in the logistics chain to effectively interact with each other and jointly respond to changing consumer demands. In some cases, we are talking about creating new approaches and replacing existing technologies aimed at achieving the set results in terms of speed and flexibility in choosing options to meet consumer demand. Thus, the analysis allows us to state that logistics mediation as a special sphere of business activity has passed the stage of formation. The prerequisites for its improvement are primarily related to the implementation of the strategy of innovative balanced development of the national economy and further development of the logistics services market. Starting with the 3PL model, all logistics service providers actively use information and communication technologies, work in both retail and e-Commerce formats, and develop on the principle of system outsourcing, creating significant added value for their customers by saving time and resources, sharing responsibilities, and responding quickly to changes in consumer preferences. We can state with confidence that if earlier logistics was considered as a function of providing business, now it determines the system way of doing business and its innovative technologies.
Warum hat es das Erbbaurecht so schwer? – Zur Erhöhung der Akzeptanz von Erbbaurechten durch mehr Marktgerechtigkeit
Authors: Löhr Dirk , Braun Oliver 
Published: May 2020

ZusammenfassungErbbaurechte werden in den letzten Jahren zwar wieder verstärkt verwendet, führen aber immer noch ein Nischendasein. Bei Erbbaurechten findet eine Aufspaltung der Eigentumsrechte an der Immobilie statt. Hierdurch entstehen einerseits zusätzliche Kontroll- und Durchsetzungskosten, andererseits auch Eingriffe in die Verfügungsrechte des Erbbauberechtigten. Beides führt zu Wertabschlägen, mit denen Volleigentum nicht belastet ist. Dies belastet sowohl die Rendite als auch die Möglichkeiten, bezahlbaren Wohnraum über Erbbaurechte zur Verfügung zu stellen. Hinzu kommen Nachteile bei der Veräußerbarkeit und der Beleihbarkeit von Erbbaurechten. Auf der anderen Seite können Erbbaurechte als ein Instrumentarium zur Reallokation von Investitionsrisiken auf den Erbbaurechtnehmer verstanden werden. Marktgerechtigkeit vorausgesetzt, sinken die Renditeforderungen der Erbbaurechtgeber stärker ab, als die Renditeforderungen der Erbbaurechtgeber ansteigen. Hierdurch entstehen u. U. beträchtliche Diskontierungsgewinne, die bei Volleigentum nicht generiert werden und die eine Überkompensation der Nachteile des Erbbaurechts bewirken können. Allerdings erlaubt es die Art und Weise, wie in Deutschland Erbbaurechte angewandt werden aber nicht, diesen potenziellen Mehrwert tatsächlich auszuschöpfen. Es werden Modelle aufgezeigt, die diese Anwendungsprobleme auf einfache Weise beheben.