bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I and randomized phase II etctn study of KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab) in relapsed and refractory diffuse large B-cell lymphoma.
Authors: Joffe Erel , Vardhana Santosha Adipudi , Kumar Anita , Abedi Mehrdad , Hoeg Rasmus , Sharon Elad , Younes Anas 
Published: May 2020

TPS8072 Background: Diffuse large B-cell lymphoma (DLBCL) escapes host immune responses via inhibition of the B2M and CD58 pathways and upregulation of PD-1 ligands. However, treatment results with PD-1 blockade have been disappointing. One potential mechanism is the recruitment of intra-tumoral regulatory T-cells (Tregs) which suppress anti-tumor immunity and inhibit NK cell cytotoxicity. Targeting regulatory T cells with the CCR4 antibody mogamulizumab (KW-0761) represents a molecularly informed strategy to overcome this resistance. Mogamulizumab has been safely administered in combination with pembrolizumab (MK-3475) in patients with solid malignancies and may promote CD8 T-cell dependent effector and NK cell-dependent cytotoxicity in lymphomas. Methods: This is a multi-center NIH-ETCTN phase Ib/randomized phase II study. The phase I will evaluate the safety and tolerability of mogamulizumab in combination with pembrolizumab in patients with R/R DLBCL and determine the recommended phase II dose (RP2D). A traditional 3+3 design with a starting dose of pembrolizumab 200mg IV on day 1 of a 21-day cycle and mogamulizumab 1mg/kg IV on days 1, 8, 15 and then 1.5 mg/kg IV every 21 days. The phase II will evaluate the efficacy of the combination by PFS (primary endpoint) ORR and CR (secondary endpoints). This will be a randomized 1:1 study with allowed crossover, comparing the combination to single agent pembrolizumab Correlative studies will evaluate the association of tumor infiltrating CD8 and NK cells with response to treatment, somatic mutations in B2M and CD58 and with MHC-I expression on DLBCL cells. Functional characterization of circulating immune cells in the peripheral blood and measurement of pro and anti-inflammatory cytokines will be used to assess the levels, activation status and effector function of Tregs and circulating T cells. Inclusion criteria include measurable disease, ≥2 prior lines of therapy including or ineligible for autologous stem cell transplant, ECOG ≤ 2 and normal organ function. Prior or planned allogeneic stem cell transplant, as well as prior treatment with an anti PD-1/PD-L1/CTLA4 antibody, preexisting autoimmune disease or CNS involvement by lymphoma are exclusion criteria. The study aims to enroll up to 12 patients on the phase I and up to 58 patients on the phase II and can be opened at any ETCTN participating site. To date it has been opened at two sites and is accruing the first patients for the phase I portion. Clinical trial information: NCT03309878 .
Phase I/II study of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) with lenalidomide (R2-ICE) in patients with first-relapse/primary refractory diffuse large B-cell lymphoma (DLBCL) in academic and community cancer research united (ACCRU) network.
Authors: Guerra-Bauman Francis , LaPlant Betsy , Macon William R. , Witzig Thomas E. , Farooq Umar , Nowakowski Grzegorz S. , Feldman Tatyana 
Published: May 2020

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .
Open-label pilot study of genetically engineered NY-ESO-1–specific t cells (GSK3377794) alone or in combination with pembrolizumab in relapsed/refractory multiple myeloma.
Authors: Rapoport Aaron , Hoffman James Edward , Kaufman Jonathan L. , Blouch Kristin , Butler Emily , Deyoung Maurice Phillip , Farsaci Benedetto , Hasan Aisha N. , Holmes Andrew P. , Huff Anne , Jain Amit , Chisamore Michael Jon , Nishihori Taiga 
Published: May 2020

TPS8555 Background: Adoptive cellular therapy may be practice-changing in relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A*02. GSK3377794 has shown clinical activity in synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and MM after autologous stem cell transplant. NY-ESO-1 and LAGE-1a are cancer/testis antigens frequently overexpressed in MM and linked to poor clinical outcome. PD-1 expression on CD8 T cells, which has been observed in MM patients previously treated with GSK3377794 as well as with CD19 CAR T-cell therapy, can limit adaptive immune response. We hypothesize that GSK3377794 alone, or in combination with the anti-PD-1 inhibitor pembrolizumab, may result in an antitumor effect in MM. Methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients with relapsed/refractory MM positive for HLA-A*02:01, HLA-A*02:05, ± HLA-A*02:06 and NY-ESO-1/LAGE-1a. Patients (n = 20) who have received ≥3 prior therapies containing ≥1 immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, or glucocorticoid will be assigned to either single-infusion GSK3377794 (Arm 1, n = 10) or single-infusion GSK3377794 + pembrolizumab 200 mg IV every 3 weeks (Arm 2, n = 10). Arm 1 enrollment will be completed first. In Arm 2, pembrolizumab will begin in Week 3 (Week 6 if precluded by toxicity). Patients in both arms will provide cells via leukapheresis to manufacture autologous NY-ESO-1–specific T cells, undergo lymphodepletion (fludarabine + cyclophosphamide), and then receive GSK3377794 infusion (1−8x109 transduced T cells). Primary and secondary objectives are to assess safety/tolerability and antitumor activity, respectively, of GSK3377794 (± pembrolizumab). Arm 2 enrollment will pause for a 3-week safety review after 3 patients have received a first dose of pembrolizumab. Efficacy, safety, and biomarkers will be assessed every visit. The treatment phase will last 108 weeks, or until disease progression; follow-up will last ≤15 years. As of January 2020, 3 patients have been treated. Funding: GlaxoSmithKline (208470) Clinical trial information: NCT03168438 .
RESILIENT part II: an open-label, randomized, phase III study of liposomal irinotecan injection in patients with small-cell lung cancer who have progressed with platinum-based first-line therapy.
Authors: Paz-Ares Luis G. , Spigel David R. , Chen Yuanbin , Jove Maria , Juan-Vidal Oscar , Rich Patricia , Hayes Theresa M. , Gutierrez Calderon M Vanesa , Bernabe Caro Reyes , Navarro Alejandro , Dowlati Afshin , Zhang Bin , Moore Yan , Wang Haofei Tiffany , Kokhreidze Jaba , Ponce Aix Santiago , Bunn Paul 
Published: May 2020

TPS9081 Background: Although small cell lung cancer (SCLC) is often sensitive to established first-line therapies, many patients relapse and develop drug resistance, and second-line therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Preliminary data from the dose-ranging part of the study (part 1) showed that liposomal irinotecan 70 mg/m2 administered every 2 weeks was well tolerated and had promising antitumor activity (Paz-Ares et al. ASCO 2019; poster 318). Here, we present the design of the second, larger part of the study, which will evaluate the efficacy and safety of liposomal irinotecan versus topotecan in the same patient population. Methods: Part 2 of RESILIENT is a phase 3, open-label study with a planned sample size of 450. Patients are randomly allocated 1:1 to intravenous liposomal irinotecan or intravenous topotecan. Liposomal irinotecan is administered every 2 weeks at 70 mg/m2 (free-base equivalent) and topotecan is administered for 5 consecutive days every 3 weeks at 1.5 mg/m2. As of January 2020, 80 patients have been enrolled in part 2 of the trial. Tumor assessments are performed using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Response Assessment in Neuro-oncology criteria for CNS lesions; symptom improvement is measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Safety assessments include monitoring for adverse events. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free survival (PFS), objective response rate, and proportion of patients reporting symptom improvement. Patients will continue study treatment until disease progression, unacceptable toxicity or study withdrawal and will then be followed for survival until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT03088813.
Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy.
Authors: Johnson Melissa Lynne , Chadjaa Mustapha , Yoruk Semra , Besse Benjamin 
Published: May 2020

TPS9625 Background: Despite recent advances in the treatment of NSQ NSCLC, including the integration of immune checkpoint inhibitors (ICI) into first-line treatment of all patients, novel therapies are necessary at disease progression. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), a cell-surface glycoprotein, is overexpressed in several tumor types, including NSQ NSCLC; ~20% of patients express high CEACAM5 levels. SAR408701 is an ADC combining a humanized antibody targeting CEACAM5 with the potent cytotoxic maytansinoid derivative DM4 and is expected to selectively deliver DM4 to CEACAM5-expressing cancer cells. In an interim analysis of a first-in-human study (NCT02187848) in patients with NSQ NSCLC and CEACAM5 expression in ≥50% of tumor cells, SAR408701 administered 100 mg/m² every 2 weeks showed an objective response rate (ORR) of 23% and a favorable safety profile (Gazzah A et al J Clin Oncol. 2019;37:15, 9072). Methods: In this randomized, open-label, phase 3 trial, patients receive either SAR408701 100 mg/m² IV every 2 weeks or the standard of care treatment docetaxel 75 mg/m² IV every 3 weeks. Randomization is stratified on ECOG performance status (PS), previous ICI treatment (sequential vs combination), and geographical region. Patients are ≥18 years with metastatic NSQ NSCLC after platinum-based chemotherapy and ICI treatment (anti-PD-1/PD-L1 monoclonal antibody), express CEACAM5 in ≥50% of tumor cells at ≥2+ intensity (central testing), and have ECOG PS 0–1. Exclusion criteria include untreated brain metastases, history of corneal disorders, and prior treatment with docetaxel, maytansinoid derivatives, or CEACAM5-targeting drugs. Tumor imaging occurs at baseline and every 8 weeks until disease progression. Primary endpoints are progression-free survival (PFS; RECIST v1.1 by independent blinded review committee) and overall survival (OS), both analyzed by Kaplan-Meier method, stratified log-rank test, and stratified Cox proportional hazard model. Study success is defined either on PFS or OS, with a strong type-I error control for multiple hypotheses. Secondary endpoints are ORR and duration of response (RECIST v1.1), health related quality of life (EORTC QLQ-C30 and EORTC QLQ-LC13), and safety (adverse events graded by NCI CTCAE v5). Approximately 554 randomized patients (277 per arm) is adequate to reach both PFS and OS events. The study opened in Nov 2019, and as of Feb 7, 2020, 20 sites in 8 countries are activated. Clinical trial information: NCT04154956 .
AcceleRET Lung: A phase III study of first-line pralsetinib in patients (pts) with RET-fusion+ advanced/metastatic non-small cell lung cancer (NSCLC).
Authors: Besse Benjamin , Felip Enriqueta , Clifford Corinne , Louie-Gao Melinda , Green Jennifer , Turner Christopher D. , Popat Sanjay 
Published: May 2020

TPS9633 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1-2% of NSCLC, but no selective RET inhibitors are approved for use. The investigational RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multikinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), pts with RET-fusion+ NSCLC treated with 400 mg once daily (QD) of pralsetinib (N = 80) after platinum-based chemotherapy achieved an overall response rate (ORR) of 61% (95% CI 50, 72; 2 responses pending confirmation) per independent central review. In addition, a promising ORR of 73% (all centrally confirmed responses) was attained in the treatment naïve cohort (N = 26). Most treatment-related adverse events were grade 1-2 across the entire safety population treated at 400 mg QD (N = 354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). Methods: Approximately 250 pts with metastatic RET-fusion+ NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and ECOG PS. Key eligibility criteria include no prior systemic treatment for metastatic disease; RET-fusion+ tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per RECIST v1.1. Pts randomized to SOC will be permitted to cross-over to receive pralsetinib upon disease progression. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Recruitment has begun with sites (active or planned) in North America, Europe and Asia. Clinical trial information: NCT04222972 .
A phase II study of atezolizumab and cobimetinib in PD-1/PD-L1 inhibitor resistant or refractory non-small cell lung cancer: ETCTN #10166.
Authors: Liu Stephen V. , Hall Richard Delmar , Saltos Andreas Nicholas , Otterson Gregory Alan , Tan Ming Tony , Gnjatic Sacha , Gentzler Ryan D. , Tanvetyanon Tawee , Chen Helen X. , Sharon Elad 
Published: May 2020

TPS9638 Background: Use of checkpoint inhibitors, alone or with chemotherapy, has emerged as the preferred standard treatment for patients with advanced, driver-negative non-small cell lung cancer (NSCLC). While outcomes are superior to chemotherapy alone, only a subset of patients achieve durable response and long term survival. One potential mechanism of primary resistance to checkpoint inhibitors is the lack of tumor-infiltrating lymphocytes. Inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) increases the number of CD8+ T-cell within a tumor and has shown synergy with anti-programmed death-ligand 1 (PD-L1) antibodies. The combination of the MEK inhibitor cobimetinib and the PD-L1 antibody atezolizumab has led to limited responses in colorectal cancer, a tumor typically non-responsive to checkpoint inhibition. This phase II trial explores the combination of cobimetinib and atezolizumab in patients with PD(L)1-refractory NSCLC. Methods: This phase II study is being conducted through the Experimental Therapeutics Clinical Trials Network (ETCTN #10166). Eligible patients have advanced NSCLC with primary resistance to anti-PD(L)1 therapy (defined as progression noted within 6 months of initiating therapy) and tumor amenable to serial core biopsy. Patients will receive atezolizumab 840mg intravenously every 2 weeks and cobimetinib 60mg orally for 21 days in 28-day cycles. Two cohorts will enroll in parallel, defined by presence or absence of a KRAS mutation. Each cohort will employ a Simon two-stage design to test a null rate of 5% vs. 25% (power = 0.90, □ = 0.10). If > 1 of 9 patients in stage 1 achieve a partial response, an additional 15 patients are enrolled and if > 3 patients achieve a durable response, the combination will be worthy of further investigation. The primary endpoint is durable (> 6 months) response rate. Secondary endpoints are overall response rate, progression free survival, overall survival, duration of response and adverse events. Biopsies performed at baseline and after 3 weeks of therapy will assess the change in the density of tumoral CD8+ T-cells. Whole exome sequencing and immune cell profiling will also be performed on serial samples. Enrollment was initially limited to KRAS-mutant NSCLC. Prespecified activity goal for the first stage of accrual has been met; second stage accrual began in September 2019. Enrollment to the KRAS wild-type cohort will commence. Clinical trial information: NCT03600701 .
Nuclear Receptor Coactivators (NCOAs) and Corepressors (NCORs) in the Brain
Authors: Sun Zheng , Xu Yong 
Published: May 2020

Abstract
Nuclear receptor coactivators (NCOAs) and corepressors (NCORs) bind to nuclear hormone receptors in a ligand-dependent manner and mediate the transcriptional activation or repression of the downstream target genes in response to hormones, metabolites, xenobiotics, and drugs. NCOAs and NCORs are widely expressed in the mammalian brain. Studies using genetic animal models started to reveal pivotal roles of NCOAs/NCORs in the brain in regulating hormonal signaling, sexual behaviors, consummatory behaviors, exploratory and locomotor behaviors, moods, learning, and memory. Genetic variants of NCOAs or NCORs have begun to emerge from human patients with obesity, hormonal disruption, intellectual disability, or autism spectrum disorders. Here we review recent studies that shed light on the function of NCOAs and NCORs in the central nervous system.
Emergence From the COVID-19 Pandemic and the Care of Chronic Pain: Guidance for the Interventionalist
Authors: Deer Timothy R. , Sayed Dawood , Pope Jason E. , Chakravarthy Krishnan V. , Petersen Erika , Moeschler Susan M. , Abd-Elsayed Alaa , Amirdelfan Kasra , Mekhail Nagy ,   the ASPN COVID Workgroup
Published: May 2020

BACKGROUND:
The current coronavirus disease 2019 (COVID-19) pandemic led to a significant disruption in the care of pain from chronic and subacute conditions. The impact of this cessation of pain treatment may have unintended consequences of increased pain, reduced function, increased reliance on opioid medications, and potential increased morbidity, due to the systemic impact of untreated disease burden. This may include decreased mobility, reduction in overall health status, and increase of opioid use with the associated risks.

METHODS:
The article is the study of the American Society of Pain and Neuroscience (ASPN) COVID-19 task force to evaluate the policies set forth by federal, state, and local agencies to reduce or eliminate elective procedures for those patients with pain from spine, nerve, and joint disease. The impact of these decisions, which were needed to reduce the spread of the pandemic, led to a delay in care for many patients. We hence review an emergence plan to reinitiate this pain-related care. The goal is to outline a path to work with federal, state, and local authorities to combat the spread of the pandemic and minimize the deleterious impact of pain and suffering on our chronic pain patients.

RESULTS:
The article sets forth a strategy for the interventional pain centers to reemerge from the current pandemic and to set a course for future events.

CONCLUSIONS:
The COVID-19 pandemic represents an overwhelming challenge to interventional pain physicians and their patients. In addition to urgent actions needed for disease mitigation, the ASPN recommends a staged return to pain management professionals’ workflow.
Management Consulting In The Digital Economy
Authors: Mrochkovskiy N. 
Published: May 2020

The article discusses the transformation of management consulting in the digital economy: the functions of management consulting and the reasons for the impact of consulting on the functioning and development of business entities are determined.
The author classified the types of management consulting in the digital economy as a special form of organizations. In particular, the following classification features were identified: regularity, nature of interaction, degree of standardization, nature of integration of a consultant and a recipient of services, method of payment for consultant services, formalization of consulting services.
The article also provides an overview of opportunities for intensifying and increasing the level of financial and economic efficiency of consulting services.