bluuebunny/crossref_metadata_2025 huggingface dataset:
DUO-E/GOG-3041/ENGOT-EN10: a randomized phase III trial of first-line carboplatin (carb) and paclitaxel (pac) in combination with durvalumab (durva), followed by maintenance durva with or without olaparib (ola), in patients (pts) with newly diagnosed (nd) advanced or recurrent endometrial cancer (EC).
Authors: Westin Shannon Neville , Moore Kathleen N. , Van Nieuwenhuysen Els , Oza Amit M. , Mileshkin Linda R. , Okamoto Aikou , Suzuki Akiko , Meyer Kassondra , Barker Laura , Rhee Joon , Vergote Ignace
Published: May 2020

TPS6108

Background: There is a high unmet need for advances in EC treatment that provide progression-free survival (PFS) and overall survival (OS) benefits. EC tumors are sensitive to carb/pac (Pectasides et al. Gynecol Oncol 2008). Maintenance therapy with the poly(ADP-ribose) polymerase inhibitor (PARPi) ola (with or without bevacizumab) led to significant PFS benefits in advanced ovarian cancer pts with either nd (SOLO1, Moore et al. NEJM 2018; PAOLA-1, Ray-Coquard et al. NEJM 2019) or recurrent (SOLO2, Pujade-Lauraine et al. Lancet Oncol 2017; Study 19, Friedlander et al. Br J Cancer 2018) platinum-sensitive disease, regardless of BRCA mutation status (PAOLA-1; Study 19), and in BRCA-mutated metastatic pancreatic cancer pts (POLO, Golan et al. NEJM 2019). Molecular features of EC could predict sensitivity to PARPi (de Jonge et al. Clin Cancer Res 2019; Auguste et al. Mod Pathol 2018). PARPi has been shown to prime the immune microenvironment in a preclinical BRCA1 mutant ovarian model (Higuchi et al. Cancer Immunol Res 2015). Clinical trials have demonstrated antitumor activity of the anti-programmed cell death ligand-1 (anti-PD-L1) blocker durva (Antill et al. J Clin Oncol 2019) and anti-programmed cell death-1 (anti-PD-1) antibody therapies (Makker et al. ESMO 2019; Oaknin et al. SGO 2019) in EC pts. The DUO-E trial (EUDRACT 2019-004112-60, D9311C00001, NCT04269200) will investigate whether the addition of durva to carb/pac, followed by durva (with or without ola) maintenance treatment, improves PFS in pts with nd advanced or recurrent EC. Methods: Eligible pts for this multicenter, double-blind, Phase III trial must have nd Stage III/IV or recurrent EC and be naïve to first-line chemotherapy. Pts will be randomized (1:1:1; n=~233 per arm) to: arm A) carb/pac + placebo (pbo) (q3w for six cycles) followed by pbo maintenance treatment; arm B) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + pbo (tablets bid); or arm C) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + ola (300 mg bid tablets). Pts received maintenance treatment until disease progression. Primary endpoint: investigator-assessed PFS (RECIST 1.1) of arm B vs. arm A. Key secondary endpoints: PFS of arm C vs. arm A; OS of arm B vs. arm A, and of arm C vs. arm A. Enrollment began in Q1 2020. Clinical trial information: 2019-004112-60.
INDUCE-3: A randomized, double-blind study of GSK3359609 (GSK609), an inducible T-cell co-stimulatory (ICOS) agonist antibody, plus pembrolizumab (PE) versus placebo (PL) plus PE for first-line treatment of PD-L1-positive recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Hansen Aaron Richard , Stanton Thomas S. , Hong Min Hee , Cohen Ezra E.W. , Mehanna Hisham Mohamed , Chisamore Michael Jon , Turner David , Yadavilli Sapna , Bell Kelly , Baccan Carlos , Leone Rosalida , Chen Helen , Zhou Helen , Ellis Catherine Elizabeth , Ballas Marc S. , Hoos Axel , Rischin Danny
Published: May 2020

TPS6591

Background: Pembrolizumab as part of first-line treatment for patients (pts) with R/M HNSCC has improved survival. However, in order to further improve outcomes in this population investigation of rational combinations targeting different mechanisms that cancers exploit to evade the immune system is required. ICOS, a member of the CD28/B7 immunoglobulin receptor superfamily, provides a co-stimulatory signal augmenting T-cell proliferation, cytokine production, cytotoxic function and survival. GSK609 is a humanized IgG4 antibody selected for its potent agonist activity and non-depleting properties. The rationale for targeting ICOS with GSK609 plus PD-1 blockade with PE is supported by preclinical and clinical evidence (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). INDUCE-3 trial (NCT04128696) will explore if the addition of GSK609 to PE improves outcomes of pts with R/M HNSCC. Methods: INDUCE-3 uses a 2-in-1 adaptive design that has the option to seamlessly expand from an initial Phase 2 to a Phase 3 study. Pts (n = 600) will be stratified by PD-L1 status and HPV status (oropharynx only) then randomly assigned in a 1:1 ratio to receive GSK609 plus PE or PL plus PE, every 3 weeks until progression, unacceptable toxicity, or up to 35 cycles. GSK609 plus PE will be assessed for superiority versus PL plus PE in overall survival (OS) and progression-free survival (PFS) per RECISTv1.1 as dual primary endpoints; secondary endpoints include PFS per immune-based RECIST; milestone OS; safety and tolerability; time to deterioration in patient-reported physical function and pain. Efficacy and patient-reported outcome endpoints will be assessed in the PD-L1 combined positive score (CPS) ≥1 and ≥20 populations. Key eligibility criteria are aged ≥18 years; locally incurable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; no prior systemic therapy in the R/M setting; PD-L1 CPS ≥1 by central testing; measurable disease per RECIST v1.1 and ECOG PS 0/1. Recruitment is ongoing in countries across the globe. Funding: Study is funded by GlaxoSmithKline and in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial information: NCT04128696 .
Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with pan-refractory, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Roe Denise , Saba Nabil F. , Bauman Jessica Ruth , Kaczmar John M. , Burtness Barbara , Muzaffar Jameel , Julian Ricklie Ann , Wang Steven , Bearelly Shethal , Baker Audrey , Steuer Conor Ernst , Bhatia Aarti K. , Giri Anshu , Caulin Carlos , Stabile Laura P. , Centuori Sara , Chung Christine H.
Published: May 2020

TPS6594

Background: Patients with pan-refractory R/M HNSCC, with clinical resistance to cytotoxic therapy, anti-EGFR molecular targeting, and immunotherapy, have poor survival. An established tumor-intrinsic resistance mechanism to cetuximab, an anti-EGFR IgG1 monoclonal antibody (mAb), is activation of the hepatocyte growth factor (HGF)/cMet pathway, which converges with the EGFR network at both the PI3K/Akt and MAPK nodes allowing for reciprocal compensation. Moreover, over-expression of HGF in the tumor microenvironment is immunosuppressive. Convergent data suggest that HGF/cMet pathway inhibition concurrent with EGFR blockade may overcome cetuximab resistance. We previously reported a Phase I study of ficlatuzumab, a humanized anti-HGF IgG1 mAb, with cetuximab in cetuximab-resistant R/M HNSCC. The combination showed promising safety, overall response rate (ORR) and progression-free survival (PFS). Preliminary biomarker analyses showed that high circulating cMet was associated with poor PFS whereas serum Veristrat, a proteomic classifier associated with worse prognosis in the setting of anti-EGFR monotherapy, was not. An increase in total peripheral T cells, particularly the CD8+ subset, was associated with treatment response while progression was associated with expansion of a unique myeloid population. We designed a follow-on randomized phase II trial evaluating ficlatuzumab with or without cetuximab in pan-refractory, R/M HNSCC with signaling and immune correlatives. Methods: This is a multicenter phase II trial with a randomized, non-comparative, two-arm design (ficlatuzumab 20 mg/kg with or without cetuximab 500 mg/m2 every 2 weeks) in patients with pan-refractory R/M HNSCC. Key eligibility criteria include: R/M HNSCC; cetuximab resistance (progression during or within 6 months of cetuximab-radiation or palliative cetuximab); platinum resistance; prior exposure to anti-PD1 mAb; ECOG 0-1; consent to baseline research biopsy. The primary objective is to evaluate the efficacy of each arm as measured by PFS. To test the hypothesis that either regimen improves historical PFS from 2 to 3.33 months requires 66 eligible patients. Key secondary endpoints are ORR and survival. Mechanistic biomarkers include tumor HGF/cMet pathway activation, tumor and peripheral immune profiles, soluble cMet, and serum Veristrat. Thirty-five of 66 subjects have enrolled at 6 centers. A Bayesian continuous monitoring rule for futility has not been triggered for either arm. Clinical trial information: NCT03422536 .
ROMAN: Reduction in oral mucositis with avasopasem manganese (GC4419)–Phase III trial in patients receiving chemoradiotherapy for locally advanced, nonmetastatic head and neck cancer.
Authors: Holmlund Jon , Brill Jeffrey Mark , Fairbanks Robert , Saunders Deborah , Sonis Stephen T. , Downs Matt , Anderson Carryn M.
Published: May 2020

TPS6596

Background: Approximately 70% of patients receiving intensity-modulated radiotherapy (IMRT) plus cisplatin for locally advanced head and neck cancer (HNC) develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring enteral nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by converting superoxide to H2O2. It showed promising reduction of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). In a subsequent randomized, double-blind placebo-controlled trial in 223 patients receiving IMRT/cisplatin for HNC (ASCO 2018), 90 mg of GC4419 administered M-F prior to IMRT demonstrated statistically significant reduction in SOM duration (p=0.024, median 1.5 days @ 90 mg vs. 19 days placebo) and meaningful reductions @ 90 mg in SOM incidence (43% vs. 65%) and severity (incidence of Grade 4, 16% vs. 30%). The safety results were acceptable and consistent with the known toxicities of IMRT/cisplatin. Methods: 335 patients at multiple centers in the U.S. and Canada with locally-advanced, nonmetastatic head and neck cancer (oral cavity/oropharyngeal) receiving 70 Gy IMRT (>50 Gy to > 2 oral sites) plus cisplatin (40 mg/m2 qwk x 6-7, or 100 mg/m2 q3wk x 3) are being randomized (double-blinded) 3:2 to 90 mg of GC4419 or placebo, M-F before each RT fraction. Enrollment is stratified by cisplatin schedule and treatment setting (definitive vs. post-op). OM by the WHO scale will be assessed twice weekly during RT & weekly for 2 weeks post RT. The primary efficacy endpoint is incidence of SOM through the end of IMRT. Secondary efficacy endpoints include severity (incidence of Grade 4 OM through the end of IMRT), & days of SOM (days from first to last SOM for all patients, with patients never developing SOM having 0 days of SOM by definition). Days of SOM for the subset developing SOM will be analyzed descriptively. Patients will be followed for one year post IMRT for tumor progression/recurrence and for two years for survival. Clinical trial information: NCT03689712 .
A phase I/II study of IMGN632, a novel CD123-targeting antibody-drug conjugate, in patients with relapsed/refractory acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, and other CD123-positive hematologic malignancies.
Authors: Daver Naval Guastad , Montesinos Pau , DeAngelo Daniel J. , Wang Eunice S. , Todisco Elisabetta , Tarella Corrado , Martinelli Giovanni , Erba Harry Paul , Deconinck Eric , Sweet Kendra L , Walter Roland B. , Levy Moshe Yair , Pemmaraju Naveen , Lane Andrew A. , Rizzieri David , Konopleva Marina , Sloss Callum Mortimer , Wang Jiuzhou , Malcolm Kara E , Zweidler-McKay Patrick A
Published: May 2020

TPS7563

Background: Overexpression of CD123 occurs in multiple hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute lymphoblastic leukemia (ALL) and others, thus making this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprising a novel anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating cytotoxic payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class. Preclinically, IMGN632 has demonstrated potent activity against AML, BPDCN and ALL models, with a wide therapeutic index in animal models, as well as a 150-fold differential cytotoxicity in AML patient samples compared to normal hematopoietic progenitors (PMIDs: 29661755, 30361418). Remarkable sensitivity of BPDCN patient derived xenografts to IMGN632 has been demonstrated (Blood 2018 132:3956). Methods: This Phase I/II study comprises a dose escalation phase designed to establish the recommended phase II dose (RP2D) for IMGN632, as well as dose expansion cohorts to further explore the safety and preliminary anti-leukemia activity of IMGN632. Expansion cohorts were designed to evaluate the following patient populations: adult patients with relapsed or refractory BPDCN or patients with untreated BPDCN who are inappropriate for available therapies, patients with relapsed or refractory AML, or with other CD123+ relapsed or refractory hematologic malignancies including ALL. Inclusion criteria include up to four prior lines of therapy which may include transplant. Patients with active central nervous system disease, history of veno-occlusive disease of the liver, or history of grade IV capillary leak syndrome or non-cardiac grade IV edema are ineligible. Expansion cohorts for unfit frontline and relapsed/refractory BPDCN, and relapsed/refractory ALL continue to enroll at the RP2D (0.045 mg/kg Q3W). Clinical trial information: NCT03386513 .
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

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.
Directions of Development of the Mineral Fertilizer Industry in the Digital Age
Authors: Kulyasova E. , Kulyasov N. , Grinev N.
Published: May 2020

This article is devoted to the development of a model for enhancing the development of the mineral fertilizer industry, which involves the use of a sequentially-parallel approach to implement state support measures and digital transformation of enterprises in this industry. Currently, there is a growing influence of Industry 4.0 and digital technologies on enterprises of the mineral fertilizer industry. These enterprises are of strategically important economic interest for the national economy, as they are objects whose hallmarks are their large-scale, high-tech, high level of dependence on environmental conditions. An analysis of the level of development of the mineral fertilizer industry made it possible to identify a high level of export orientation of the products of enterprises in this industry. The digital transformation of the mineral fertilizer industry is currently hampered by the one-sidedness of the adopted state programs for the development of the industry, which are based on an extensive increase in production capacities that can gradually solve the problem of physical deterioration of fixed assets, but which does not provide an effective institutional environment that stimulates the creation of innovations and the introduction of digital technologies. While the experience of leading countries indicates that the implementation of the Industry 4.0 concept, aimed at the widespread adoption of digitalization processes, can increase the organization’s innovative potential and ensure the world level of competitiveness of mineral fertilizer products. A model for enhancing the development of the mineral fertilizer industry is proposed, based on the use of a sequentially-parallel method in the development and implementation of a set of measures, the implementation of which covers all levels of management both to create and maintain a favorable innovative climate in the framework of macroeconomics as a whole, and to develop the interaction of participants in the industry level and at the level of industrial enterprises themselves.
Modern Trends in the Transformation of the Industrial Framework of the Russian Economy in the Context of Digitalization and Industry 4.0
Authors: Morkovkin D.
Published: May 2020

The defining trend of the ongoing Fourth industrial revolution based on Industry 4.0 is the digitalization of technological processes for creating new value in material production. The introduction of global trends of the "Industry 4.0" concept into the practice of functioning of domestic enterprises, the importance of global trends for the domestic industry require the search for new scientific approaches to research and systematize the manifestations of digitalization, taking into account risks and dangers, and developing appropriate industrial policy measures. The study analyzes the main technologies and tools of the Industry 4.0 concept, as well as the possibilities of its use for the progressive transformation of the Russian industrial complex. Modern trends and promising directions of innovative transformation of the industrial sector of the Russian economy are identified, taking into account the identified specific features of Industry 4.0.
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.
Euthanasia: not an every day experience
Authors: Shaw Charlotte Elizabeth
Published: May 2020

Euthanasia can be a very personal and often dreaded time for veterinary clients. As veterinary professionals we carry out euthanasias on a weekly or even daily basis and are therefore liable to suffer from compassion fatigue, potentially leading to burnout or apathetic behaviour. Behaviours such as these could have a negative effect on the care given during euthanasia visits. The aim is to make the 30–40 minute appointment that is a regular occurrence for veterinary professionals truly memorable and special for the client, as although we may not remember every euthanasia we carry out, the client will certainly remember it. Ideally the client should feel comfortable returning to the practice with other pets, although this is not always possible. This article will look at how veterinary practices can provide a memorable euthanasia visit for their clients, from the initial phone call, right through until days or even months after the appointment, using simple skills and inexpensive, but effective methods of making each visit a personalised experience.
Dones i terres catalanes medievals (segles X-XIII)
Authors: Cuadrada Coral
Published: May 2020

«Dones i terres catalanes medievals» és un estudi de llarga durada, a l’espai de la Catalunya Vella i la Nova. Les dones, majoritàriament, són dones amb poder: primer les feminae, després les dominae. Un poder que es palesa en l’assumpció de les polítiques masculines, però que, alhora, traspua autoritat, refl ectida en les polítiques femenines. L’objectiu principal, doncs, ha estat refl exionar sobre el rol de les dones al camp català als segles X-XIII.La metodologia emprada és la pròpia de la recerca històrica feminista, a més dels mètodes empírics clàssics: recull de dades arxivístiques, sistematització, tractament, comparació, exposició de resultats. Pel que fa a l’estat de la qüestió bibliogràfi ca, no hi ha referències per a l’època i l’òptica triada; per tant, aquesta anàlisi s’ha construït prenent com a base fonts primàries d’arxiu.
1.55 µm electrically pumped continuous wave lasing of quantum dash lasers grown on silicon
Authors: Xue Ying , Luo Wei , Zhu Si , Lin Liying , Shi Bei , Lau Kei May
Published: May 2020

Realization of fully integrated silicon photonics has been handicapped by the lack of a reliable and efficient III-V light source on Si. Specifically, electrically pumped continuous wave (CW) lasing and operation sustainable at high temperatures are critical for practical applications. Here, we present the first electrically pumped room temperature (RT) CW lasing results of 1.55 μm quantum dash (QDash) lasers directly grown on patterned on-axis (001) Si using metal organic chemical vapor deposition (MOCVD). Adopting a dash-in-well structure as the active medium, the growth of QDash was optimized on an InP on Si template. Incorporating the advantages of the optimized material growth and device fabrication, good laser performance including a low threshold current of 50 mA, a threshold current density of 1.3 kA/cm2 and operation at elevated temperature up to 59 °C in CW mode was achieved. Comparison of lasers grown on Si and native InP substrates in the same growth run was made. Based on the laser characteristics measured at room temperature and elevated temperatures, the QDash quality on the two substrates is comparable. These results suggest that MOCVD is a viable technique for lasers on Si growth and represent an advance towards silicon-based photonic-electronic integration and manufacturing.
Manipulating the critical gain level of spectral singularity in active hybridized metamaterials
Authors: Chen Miao , Li Zhaofeng , Tong Xin , Wang Xiaodong , Yang Fuhua
Published: May 2020

In this paper, we investigate the spectral singularity in an active hybridized metamaterial, which manifests itself as ultra-high transmission and reflection at the same frequency in the far-field. A transmission line combined with lumped element model is utilized to describe the proposed active metamaterial. With this model, we reveal that the critical gain level for triggering the spectral singularity is related to the coupling strength between different components of the system. Through optimizing the coupling coefficients between different components, we demonstrate the spectral singularity of the proposed structure at very low gain level, which can bring active metamaterials systems a step closer to their practical implementation. Furthermore, we demonstrate rapid switching between two spectral singularities at different frequencies in the same structure by adding or reducing small amount of gain. The exotic properties of the proposed sub-wavelength structure promise applications in switching, sensing, spaser and nonlinear optics areas.
A funkcionális lisztek ismertségének vizsgálata megkérdezések tükrében
Authors: Panyor Ágota
Published: May 2020

The unhealthy nutrition, wrong style of living and stress can have a major contribution to the development of certain diseases. The appearance of foodstuffs playing important role in health promotion may have a positive impact on blocking or reversing the above mentioned process. That's the reason why I chose functional food-products and the consumption habits of the functional flour. Under my examinations 1 investigated the notoriety, reputation and consumption frequency of functional flour. Besides I tried to explore the reasons resulting in the non-consumption of these food-products.
Teljesítményértékelés a gyakorlatban
Authors: Juhász Csilla
Published: May 2020

Performance management is one of the most important fields of management. For the evaluation of it, I have worked out a questionnary. In this questionnary I studied the importancy and method of performance evaluation. I hope my results may contribute to the reveal of practise of performance evaluation. Based on my examinations I have found that feedback for the employees was that factor, which was considered most important by interviewees at the study of performance appraisal objectives. The performance appraisal system is mainly influenced by corporate values and management. Of the others, the evaluation of tasks performed was highlighted as the most positively appraised factor. The person of the evaluator coincides with ruler manager of the traditional aspect, who may be a direct manager of the workplace or a superior manager. Examinations show that organizations mainly apply traditional systems and think by the traditional aspect.