bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of CD19-targeted EGFRt/19-28z/4-1BBL armored chimeric antigen receptor (CAR) modified T cells in patients with relapsed or refractory chronic lymphocytic leukemia.
Authors: Park Jae Hong , Riviere Isabelle , Wang Xiuyan , Senechal Brigitte , Bernal Yvette , Halton Elizabeth , Diamonte Claudia , Wang Yongzeng , Brentjens Renier J. , Sadelain Michel
Published: September 2018

TPS7568

Background: Despite the recent progress in the therapy of CLL with BTK, PI3Kδ, and BCL2 inhibitors, CLL remains incurable and patients with high-risk disease features (i.e. del17p, complex karyotype) and patients whose disease progress after treatment with the above targeted agents continue to have extremely poor prognosis. CD19-specific chimeric antigen receptor (CAR) T cell therapy with various 2nd generation CARs (19-28z or 19-41BBz) have demonstrated anti-tumor efficacy in CLL but the complete response (CR) rates in CLL have been suboptimal (20-45%) compared to CR rates in ALL (80-90%). The suboptimal activity of the current 2nd generation CAR T cells can be due to the inhibitory tumor microenvironment (TM) of CLL. We believe one approach to over the hostile TM is through the use of CD19-CAR T cells further modified to express a second costimulatory ligand, 4-1BBL. A binding of 4-1BBL to its cognate receptor enhances T cell proliferation, IL-2 secretion, and survival and cytolytic activity of the T cells compared to 19-28z. 19-41BBz and 1928BBz (Zhao Z et al. Cancer Cell 2015;28:415-428). Methods: This phase I dose escalating trial is a single-center clinical trial (MSKCC) to study the safety and efficacy of autologous EGFRt/19-28z/4-1BBL+ CAR T cells in patients with relapsed CLL. Given the concern for potential systemic toxicity the vector includes a "safety switch" in the form of a gene for the expression of truncated form of human epidermal growth factor receptor (EGFRt). Patients with relapsed CLL are eligible for the trial. Patients will receive conditioning chemotherapy of cyclophosphamide followed by escalating doses of CAR T cells (1x105 – 3x106 CAR T cells/kg). The primary endpoint is safety and maximum tolerated doses of the CAR T ells. Secondary objectives include response assessment by iwCLL criteria. The comprehensive treatment algorithms for CRS and neurotoxicity are based on our CAR T cell experience in other studies. The study will begin enrollment in February 2017 and enroll up to 30 patients. Clinical trial information: Pending.
A phase Ia/Ib study of a novel BTK inhibitor, DTRMWXHS-12 (DTRM-12), and combination products, with everolimus and pomalidomide, in pts with CLL or other B-cell lymphomas.
Authors: Gill Jennifer , He Wei , Schuster Stephen J. , Brander Danielle M. , Chatburn Elizabeth , Kennard Kaitlin , Anderson Barry Douglas , Nasta Sunita , Landsburg Daniel Jeffrey , Porter David L. , Napier Ellen , Latorre Tanya , Svoboda Jakub , Addis Victoria , Mato Anthony R.
Published: September 2018

TPS7570

Background: Synthetic lethality (SL) relies on the chemical inhibition of two aberrant genes to selectively kill malignant cells. SL is now a clinical reality in an era of multiple targeted agents and advanced genetic testing. We investigated small molecule combinations for SL through in vitro and in vivo screening and optimization studies (Table, US patent 20160324878) and demonstrated the potential of SL through best-in-class combinations of targeted agents, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition combined with an IMiD target multiple key signaling pathways, improve selective cell kill and address acquired drug-resistance. DTRM-555 is an optimized mechanism-based combination of the novel BTK inhibitor DTRM-12, with everolimus (E) and pomalidomide (P). In xenograft tumor models, DTRM-555 has shown superior efficacy over single agents at lower combined doses (1/18 of DTRM-12, 1/6 of E, and 1/6 of P). Methods: We are conducting a phase I, first-in-human multicenter trial exploring DTRM-555 in pts with CLL and B-cell NHL. Phase Ia consists of escalating DTRM-12 monotherapy doses. Phase Ib will explore doublet combination of DTRM-12 plus everolimus, and DTRM-555, the novel triplet combination. Safety is the primary study endpoint. Secondary endpoints include anti-tumor activity and pharmacokinetic studies. Eligible pts are > / = 18 years / ECOG < / = 1 with CLL or B-cell NHL with no available therapies. Treatment is administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. The trial commenced on 9/27/16. Phase 1a (single subject, 50/100mg respectively) has enrolled 5 pts without DLT and is currently at the 200 mg dose level. Up to 50 pts will be enrolled. Five additional sites are planned to open in the near future across the US. Clinical trial information: NCT02900716. [Table: see text]
B-MIND: MOR208 plus bendamustine (BEN) versus rituximab (RTX) plus BEN in patients with relapsed or refractory (R-R) diffuse large B-cell lymphoma (DLBCL): An open-label, randomized phase II/III trial.
Authors: Nowakowski Grzegorz S. , Belada David , Molina Lysianne , Kopeckova Katerina , Laribi Kamel , del Campo Garcia Raquel , Coiffier Bertrand , Jurczak Wojciech , Rummel Mathias J. , Hess Georg , Rosenwald Andreas , Winderlich Mark , Korolkiewicz Roman , Zinzani Pier Luigi
Published: September 2018

TPS7571

Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label, adaptive design, phase II/III study of MOR208 + BEN vs RTX + BEN in adult patients with histologically confirmed DLBCL who have relapsed after or are refractory to 1 to 3 prior lines of therapy and who are not candidates for high-dose chemotherapy and autologous SCT. At least 1 prior therapy line must have included a CD20-targeted therapy. Other key inclusion criteria: age ≥18 years; measurable disease; availability of tumor tissue for central pathology review; ECOG 0–2, and adequate major organ systems function. Key exclusion criteria: primary refractory DLBCL; central nervous system involvement, and known double/triple hit DLBCL genetics. The safety of the combination will be assessed in an initial phase II evaluation. Treatment will comprise 6 cycles of MOR208 (12 mg/kg IV) + BEN (90 mg/m2 IV) or RTX 375 mg/m2 IV + BEN. Patients achieving a response after cycle 6 will continue to receive antibody treatment for up to 18 additional cycles. Primary endpoint: progression-free survival (PFS); secondary endpoints include: best overall response, overall survival, safety, quality of life, immunogenicity and pharmacokinetics. Enrollment of 330 patients is anticipated in Europe, US and Asia-Pacific countries. Fourteen patients have been randomized to date. Clinical trial information: NCT02763319.
A multicenter, randomized, double-blind, placebo-controlled phase III study of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, in combination with rituximab versus placebo in combination with rituximab in patients with treatment-naive follicular lymphoma (PERSPECTIVE).
Authors: Fowler Nathan Hale , Flinn Ian , Rule Simon , Chen Robert W. , Kwei Long , Beaupre Darrin M. , Chu Alvina D. , Gordon Leo I.
Published: September 2018

TPS7576

Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. A limited number of chemotherapy-free options exist for patients with treatment-naïve (TN) FL who are older or who have comorbidities. Single-agent rituximab is considered a treatment option for elderly or infirm patients. In a phase 2 study, frontline treatment with ibrutinib in combination with rituximab for 4 weekly doses without maintenance resulted in an ORR of 85% (CR, 35%) with a median follow-up of 22 months and an 18-month PFS rate of 87% (Fowler Blood 2016). The phase 2 study serves as the basis for the randomized, double-blind, placebo-controlled phase 3 PERSPECTIVE (PCYC-1141-CA) trial. PERSPECTIVE will be conducted in two parts and will uniquely test (1) whether frontline treatment with ibrutinib in combination with rituximab results in prolongation of PFS compared to rituximab alone, and (2) whether continuous versus finite treatment with ibrutinib affects PFS outcomes. Methods: In the ongoing PERSPECTIVE trial, approximately 440 patients with TN FL meeting at least one Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion will be randomized if they also meet one of the following criteria: age ≥70 years or age 60 to 69 with one or more comorbidities (creatinine clearance 30-59 mL/min or ECOG performance status of 2). Patients will be randomized to receive either ibrutinib or oral placebo once daily. All patients will be given rituximab for 4 weekly doses followed by maintenance. After at least 2 years of treatment in Part 1, patients randomized to ibrutinib who still remain on ibrutinib will be re-randomized in Part 2 to continue ibrutinib or switch to placebo. Key exclusion criteria include any prior treatment for FL, evidence of CNS involvement, or transformation. Analyses will be conducted in two distinct parts, both with a primary endpoint of PFS. The study is open for enrollment with sites planned in the US, EU, and Asia Pacific. Clinical trial information: NCT02947347.
Phase 1 study of the safety and efficacy of INCB050465 combined with obinutuzumab and bendamustine for relapsed or refractory (R/R) follicular lymphoma (FL) (CITADEL-102).
Authors: Coleman Morton , Salar Antonio , Munoz Javier , Galanina Natalie , Faivre Thea , Zinzani Pier Luigi
Published: September 2018

TPS7578

Background: Aberrant PI3Kδ activation is implicated in B-cell non-Hodgkin lymphomas (NHL) including FL, the most common indolent subtype. INCB050465, a selective PI3Kδ inhibitor, is being evaluated in an ongoing phase 1/2 study as monotherapy for r/r B-cell NHL, including FL (ASH 2016; Abstract 4195). Obinutuzumab plus bendamustine is approved for patients (pts) with rituximab-refractory FL. This phase 1 cohort expansion study will assess the safety, efficacy, and pharmacokinetics of INCB050465 combined with obinutuzumab and bendamustine in pts with r/r FL (NCT03039114). Methods: Eligible adults will have documented CD20+ FL r/r to 1–4 prior treatments (must include rituximab), ≥1 measurable lesion ( > 1.5 cm in ≥1 dimension), ECOG PS ≤2, and adequate hematologic, hepatic and renal function. Exclusion criteria will include: transformation of FL to aggressive lymphoma or receipt of allogeneic stem cell transplant (SCT) ≤6 months (or having graft-versus-host-disease after allogeneic or autologous SCT ≤3 months) before study start; receipt of any PI3K inhibitor, obinutuzumab, or bendamustine ≤12 months, or rituximab ≤1 month prior to study. Part 1 (safety run-in) will use a 3+3 design. Pts will receive INCB050465 PO at a dose of 20 mg QD continuously for 2 cycles (1 cycle = 4 wks) followed by 20 mg QW. Up to 2 dose reductions will be allowed. Pts will receive obinutuzumab 1000 mg IV (cycle 1: days 1, 8, and 15; cycles 2–6: day 1) and bendamustine 90 mg/m2 IV (cycles 1–6: days 1 and 2). In part 2 (expansion), the safety and efficacy of INCB050465 (maximum tolerated dose) plus obinutuzumab and bendamustine will be evaluated in 30 pts, including pts treated in part 1 at the dose level deemed safe and tolerated. In both parts 1 and 2, pts not progressing after 6 cycles will be maintained on INCB050465 at the dose deemed safe and tolerated, and will continue on obinutuzumab 1000 mg IV administered on Day 1 of every second cycle for an additional 24 cycles or until disease progression. Response will be assessed using Lugano criteria (FDG-PET; CT/MRI) every 12 wks until cycle 12 and every 16 wks thereafter. The trial is open for enrollment. Clinical trial information: NCT03039114.
Novel phase 1a/1b dose-finding study design of CWP232291 (CWP291) in relapsed or refractory myeloma (MM).
Authors: Yoon Sung-Soo , Manasanch Elisabet Esteve , Min Chang Ki , Kim Jin Seok , Hauptschein Robert S , Choi Jeongeun , Chun Jae Kwang
Published: September 2018

TPS8058

Background: CWP291, a novel peptidomimetic small molecule, has potent, selective inhibitory activity on a Wnt gene reporter, decreasing expression of β-catenin target genes, cyclin D1 and survivin. With broad anti-cancer efficacy in vitro, it significantly outperforms lenalidomide as a single agent combination in MM bone marrow engraftment models. Methods: This Phase 1a/1b study (NCT #02426723) was designed to define a well-tolerated dose of CWP291 as a single agent in subjects with R/R MM. CWP291 was administered IV over ≥30 minutes 2x weekly for 3 weeks out of a 4-week cycle, with standard 3+3 dose escalation design. But an important objective in terms of patient benefit and further clinical development was to explore activity of a combination regimen with lenalidomide. Thus, a novel study design allowed initiation of the Phase 1b as soon as CWP291 achieved a well-tolerated dose as a single agent. Combination therapy would start at one dose level lower. Enrollment of patients onto each arm was guided by Safety Review Committee assessments, including baseline laboratory values, performance status, extent of prior therapy, or prior adverse events related to lenalidomide. Results: Initiated September 2015, the starting dose was based on a prior Phase 1 study in AML, 198 mg/m2. There were 4 sites involved, and 11 patients enrolled over 12 months. Approval of the new design by regulatory authorities and IRBs was completed by November 2016. A well-tolerated single agent dose (297 mg/m2) was identified, allowing initiation of the Phase 1b at a dose of 198 mg/m2(one dose level lower) combined with lenalidomide. Four subjects were enrolled in ~2 months to the Phase 1b. Enrollment to both arms is continuing and the status of this study will be updated at presentation. Conclusions: The ability to consider combination therapy with a novel drug is clearly a motivation for patient participation in clinical trials; especially true in MM, as multiple new therapies are available. This trial design was approved and allowed based on assessment of individual patient safety and potential benefit. Rapid enrollment in the combination therapy arm may significantly foster development of novel agents with this study design. Clinical trial information: NCT #02426723.
Checkmate 816: A phase 3, randomized, open-label trial of nivolumab plus ipilimumab vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC.
Authors: Forde Patrick M. , Chaft Jamie E. , Felip Enriqueta , Broderick Stephen , Girard Nicolas , Awad Mark M. , Kerr Keith , Blackwood-Chirchir Anne , Yang Rong , Geese William J. , Brahmer Julie R.
Published: September 2018

TPS8577

Background: At initial diagnosis, 20% of patients (pts) with NSCLC present with early-stage disease. The 5-year overall survival (OS) rate after surgery for stage IB–IIIA NSCLC is 25%–60%. Addition of adjuvant chemotherapy to surgery only provides a 5% absolute OS benefit at 5 years. Neoadjuvant treatment with immune checkpoint inhibitors may extend OS in early-stage NSCLC by enhancing systemic immunity and eradicating micrometastatic disease. In contrast to the adjuvant setting, the neoadjuvant setting is associated with a higher tumor burden, the presence of abundant tumor antigens, and the consequent potential for tumor-associated neoantigen presentation to the immune system. In an ongoing feasibility trial in pts with stage IB–IIIA NSCLC, nivolumab (nivo; a fully human PD-1 immune checkpoint inhibitor antibody) given alone as neoadjuvant treatment induced a major pathological response (MPR; < 10% residual viable tumor cells) rate of 39% (7/18), did not delay or interfere with surgery, and was not associated with new safety signals. In a phase 1 study in pts with stage IIIB/IV NSCLC, first-line nivo + ipilimumab (ipi; a CTLA-4 immune checkpoint inhibitor antibody) showed a greater radiologic objective response rate than nivo alone (39% vs 23%). These data provided the rationale for Checkmate 816 (NCT02998528), a phase 3 study evaluating nivo + ipi vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC. Methods: Approximately 326 pts aged ≥18 years with resectable stage IB/II/IIIA NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, and Asia. Pts are ineligible if they have autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Pts will be randomized to receive nivo + ipi or platinum-doublet chemotherapy. The primary endpoint is MPR rate. Secondary endpoints include event-free survival, OS, and complete pathological response. Start date is January 2017. The estimated primary completion date is July 2019. Clinical trial information: NCT02998528.
eXalt3: A phase III study of ensartinib (X-396) in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).
Authors: Horn Leora , Wu Yi-Long , Reck Martin , Liang Chris , Tan Fenlai , Harrow Kimberly , Oertel Vance , Dukart Gary , Mok Tony
Published: September 2018

TPS8578

Background: Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile. Methods: eXalt3 (NCT02767804) is a global, randomized, open-label phase III study comparing the efficacy and safety of ensartinib to crizotinib in ALK- positive TKI naïve non-small cell lung cancer (NSCLC) patients. It is being conducted in > 100 sites in North America, South America, Europe, and the Asia/Pacific region. Enrollment began in 2016. The primary efficacy endpoint is progression free survival (PFS) assessed by independent radiology review. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. Approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized 1:1 to ensartinib 225 mg QD, or crizotinib 250 mg BID, with stratification based on prior chemotherapy, ECOG performance status (PS), CNS metastases and geographic region. Eligibility includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05. Clinical trial information: NCT02767804.
Checkmate 743: A phase 3, randomized, open-label trial of nivolumab (nivo) plus ipilimumab (ipi) vs pemetrexed plus cisplatin or carboplatin as first-line therapy in unresectable pleural mesothelioma.
Authors: Zalcman Gerard , Peters Solange , Mansfield Aaron Scott , Jahan Thierry Marie , Popat Sanjay , Scherpereel Arnaud , Hu Wenhua , Selvaggi Giovanni , Baas Paul
Published: September 2018

TPS8581

Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer with a 5-year overall survival (OS) rate of < 10%. At diagnosis, most patients (pts) have unresectable disease. Combination chemotherapy of cisplatin (or carboplatin as an alternative) + pemetrexed is the approved first-line standard of care. Phase 1 and 2 data suggest that targeting immune checkpoint pathways (eg, programmed death [PD]-1/PD-ligand 1 [PD-L1] and/or cytotoxic T-lymphocyte antigen-4 [CTLA-4]) may provide benefit with acceptable safety in MPM. In pts with previously treated, malignant mesothelioma, single-agent tremelimumab (a CTLA-4 inhibitor antibody) was active but did not improve OS vs placebo. In a phase 2 study of nivo (a fully human PD-1 immune checkpoint inhibitor antibody) in 34 pts with MPM that progressed after first-line platinum-based chemotherapy, 12-week disease control rate (DCR) was 50%, 5 pts had partial response, and 12 pts had stable disease. Given the data with single-agent CTLA-4 and PD-1 inhibitors and that CTLA-4 inhibition can induce PD-L1 expression, there is reason to anticipate synergy when combining CTLA-4 and PD-1 inhibitors in MPM. A phase 2 study assessing nivo alone and nivo + ipi (a CTLA-4 inhibitor antibody) in MPM is ongoing. CheckMate 743 (NCT02899299) is a phase 3 study that will evaluate the efficacy and safety of first-line nivo + ipi vs chemotherapy for MPM. Methods: Approximately 600 adult pts with unresectable MPM and ECOG performance status 0–1 will be randomized. Pts are ineligible if they have primary peritoneal, pericardial, or tunica vaginalis testis mesotheliomas; have active, untreated CNS metastases; or had received prior systemic therapy for pleural mesothelioma or a prior PD-1/PD-L1 or CTLA-4 checkpoint inhibitor antibody. Pts are randomized 1:1 to receive nivo + ipi or pemetrexed + cisplatin/carboplatin. Primary endpoints are OS and progression-free survival (PFS), assessed by blinded independent central review. Secondary endpoints are objective response rate (ORR), DCR, and correlation of PD-L1 expression level and efficacy (ORR, PFS, and OS). Clinical trial information: NCT02899299.
A phase 3, randomized study of first-line durvalumab (D) ± tremelimumab (T) + platinum-based chemotherapy (CT) vs CT alone in extensive disease small-cell lung cancer (ED-SCLC): Caspian.
Authors: Paz-Ares Luis G. , Jiang Haiyi , Huang Yifan , Dennis Phillip A.
Published: September 2018

TPS8586

Background: SCLC accounts for ~13% of all lung cancers and is characterized by rapid growth and early metastases development. Standard of care CT for pts presenting with ED-SCLC is associated with the development of resistance, leading to poor treatment outcomes. As such, new therapies are needed. The high mutation burden associated with SCLC provides a rationale for investigating immune checkpoint blockade in this tumor type. D is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. T is a selective human IgG2 mAb against CTLA-4. D alone and in combination with T has demonstrated a manageable safety profile and encouraging antitumor activity in non-small cell lung cancer (NSCLC). D ± T in combination with CT has also shown acceptable tolerability and preliminary signs of clinical activity in advanced NSCLC and thus may provide benefit in SCLC. Methods: CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study to determine the efficacy of CT in combination with D ± T as first-line treatment in ED-SCLC (Stage IV). Treatment-naïve pts (N = ~795; WHO/ECOG PS 0 or 1) will be randomized 1:1:1 to receive D (1500 mg) + T (75 mg) i.v. every 3 weeks (q3w) + CT (Arm 1); D (75 mg) i.v. q3w + CT (Arm 2); or CT alone (Arm 3). D ± T will be concurrently administered with CT in Arms 1 and 2 and will continue post-CT (1 further dose for T; until confirmed progressive disease for D). CT (etoposide [80–100 mg/m2] i.v. on Days 1–3 q3w + carboplatin [AUC 5–6] i.v. on Day 1 q3w or cisplatin [75–80 mg/m2] i.v. on Day 1 q3w) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. The co-primary endpoints are overall survival (OS) and progression-free survival (PFS) using blinded independent central review (RECIST v1.1), for Arm 1 vs Arm 3. Secondary endpoints include OS and PFS for Arm 2 vs Arm 3 and Arm 1 vs Arm 2, ORR, OS at 18 months, proportion of patients alive and progression free at 6 and 12 months, PK, immunogenicity, HRQoL, and safety and tolerability. Exploratory endpoints include PFS after subsequent anticancer therapy and correlation of biomarkers with response to treatment. Recruitment is ongoing. Clinical trial information: NCT03043872.
Deciphering antitumour response and resistance with intratumour heterogeneity (DARWIN II).
Authors: Hiley Crispin T. , Ahmad Tanya , Jamal-Hanjani Mariam , Abbosh Christopher , Ngai Yenting , Hackshaw Alan , Patterson Paul , Baijal Shobhit , Nicolson Marianne , Lester Jason Francis , Krebs Matthew , Ottensmeier Christian H.H , Fennell Dean Anthony , Schmid Peter , Ezhil Muthuveni , Danson Sarah , Steele Nicola L. , Middleton Gary William , Dive Caroline , Swanton Charles ,   On Behalf of the TRACERx Consortium
Published: September 2018

TPS9099

Background: The importance of intratumour heterogeneity (ITH) is increasingly recognised as a driver of cancer progression and survival outcome. However understanding how tumour clonal heterogeneity impacts upon therapeutic outcome is still an area of unmet clinical and scientific need. The TRACERx trial (NCT01888601), a prospective study of patients with radically resected primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through genetic analysis of multi-region and longitudinal tumour sampling. DARWIN II is an investigator initiated study for patients who are enrolled within the TRACERx trial, or who have multi-region sequencing of their primary disease, but subsequently relapse with metastatic disease. This study will examine the role of intra-tumour heterogeneity and predicted neo-antigens on the anti-tumour activity of anti-PDL1 immunotherapy. Methods: This multicentre non-randomised phase II molecularly stratified umbrella study will examine how clonal dominance and ITH influence outcomes after treatment, offering a unique opportunity to decipher mechanisms of resistance to immunotherapy with anti-PDL1. These data will help improve future study design by developing greater understanding of patient selection for immunotherapies in patients with NSCLC. The relationship between ITH and cfDNA/CTCs will also be explored in DARWIN II. The study arms: Arm 1: Patients either -1) without an actionable mutation and PDL1 positive or 2) without an actionable mutation and PDL1 negative following first line cytotoxic chemotherapy - Atezolizumab. Arm 2: BRAFV600 - Vemurafenib. Arm 3: ALK/RET gene rearrangement - Alectinib. Arm 4: Her2 Amplification - Trastuzumab Emtansine. Primary Outcome Measures: Progression free survival (PFS), defined as the period between the date of registration to the date of subsequent progression or death will be assessed according to: Neo-antigen burden, mutational burden, ITH as assessed using an ITH ratio index and genomic instability as assessed using a weighted genome instability index (wGII). Trial Sponsor: University College London. Clinical trial information: NCT02314481.
A phase II study of oral azacitidine (CC-486) in combination with pembrolizumab (PEMBRO) in patients with metastatic melanoma (MM).
Authors: Keung Emily , Burton Elizabeth M. , Amaria Rodabe Navroze , Glitza Isabella Claudia , Patel Sapna Pradyuman , Diab Adi , Yee Cassian , Wong Michael K , Hwu Wen-Jen , Hwu Patrick , Woodman Scott Eric , Tetzlaff Michael T. , Milton Denai , Perez Kristen , Davies Michael A. , Rai Kunal , Wargo Jennifer Ann , Tawbi Hussein Abdul-Hassan
Published: September 2018

TPS9594

Background: Immune checkpoint inhibitors have impressive response rates and improved survival for many pts with MM, offering durable responses in up to 35% of pts while others have short-lived or no response ( > 40%). A potentially targetable mechanism for immune escape is for cancers to subvert the cellular epigenetic machinery, affecting multiple aspects of the immune response from suppression of tumor antigen expression [such as Cancer Testis Antigens (CTA)] to antigen processing and presentation, thus allowing tumor proliferation to continue undetected. In preclinical models, decitabine (DAC), a DNA hypomethylating agent (HMA), has been able to revert heterogeneous CTA expression profiles, increasing cancer cell immunogenicity. HMAs also increased TH1-chemokine expression, T cell tumor infiltration, T cell-mediated tumor killing, and have been shown to be synergistic with checkpoint inhibitors in preclinical models. This suggests that epigenetic therapy with checkpoint inhibition is a rational combination to target MM. Clinical advantages of the HMA CC-486 over DAC include oral bioavailability and potential versatility in dosing and schedule. We hypothesize that CC-486 + PEMBRO will be tolerated at biologically relevant doses; enhance response to PEMBRO in pts with mm who are PD-1 naïve; and reverse resistance to immunotherapy in pts refractory/resistant to PD-1 directed therapy. Methods: This study will evaluate the safety and efficacy of CC-486 + PEMBRO defined by Objective Response Rate (ORR) by RECIST 1.1 in pts with MM. Pts who are PD-1 naïve (Arm A, n = 36) and pts who have progressed on prior PD-1 directed therapy (Arm B, n = 35) will be enrolled. Unlimited prior systemic therapies will be allowed. Pts will receive 300mg PO of CC-486 on days 1-14 and 200mg IV of PEMBRO every 3 weeks. Continuous monitoring for toxicity and futility will be performed and assumes an ORR of > 35% and > 15% for Arms A and B, respectively (95% power). Tumor biopsies at baseline and post treatment are required. Effects of CC-486 + PEMBRO on CTAs, MDSCs and Tregs, and correlation between mutation burden and response will be studied. This study is open for enrollment. Clinical trial information: NCT02816021.
SECOMBIT (sequential combo immuno and target therapy study): A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy [ipilimumab (I) /nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with metastatic melanoma and BRAF mutation.
Authors: Ascierto Paolo Antonio , Dummer Reinhard , Melero Ignacio , Palmieri Giuseppe , Giannarelli Diana , Abrami Elena , Curvietto Marcello , Simeone Ester , Grimaldi Antonio Maria
Published: September 2018

TPS9598

Background: Treatment of BRAF-mutated metastatic melanoma has dramatically changed with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune-checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). Target therapy has been associated with high response rates, but short-term responses. Conversely, treatment with immune checkpoint inhibitors was found to present with lower response rates, but long-term responses. Synergism has been demonstrated when targeted therapy is combined with immunotherapy. The risk of a high rate of toxicity limits the simultaneous combination of all the four compounds (target agents and immunomodulating monoclonal antibodies). Sequencing of these different combinations seems to be more feasible; finding the right treatment sequence represents an important issue to be addressed. Methods: Approximately, 230 patients with untreated, histologically-confirmed advanced melanoma (measurable disease by RECIST v1.1) and carrying the BRAFV600 mutation will be randomized to Arm A [E+B until disease progression (PD), followed by I+N], or Arm B (I+N until PD, followed by E+B) or Arm C (E+B for 8 weeks, followed by I+N until PD, followed by E+B until PD). Patients will receive the combo treatments with the following schedules: target therapy, E 450mg p.o. od + B 45mg p.o. bid; immunotherapy, I 3mg/kg + N 1mg/kg Q3w x 4 cycles, followed by N 3mg/kg Q2w. The OS (time from the date of randomization until death from any cause) is primary efficacy endpoint of the study. Secondary endpoints include total PFS (time from randomization until the second progression), survival at 2 and 3 years, best overall response rate, duration of response. About 90 patients will take part in the ancillary study for the evaluation of biomarkers on the biological samples available (biopsies + blood samples). 30 Sites in Europe will concur to enroll the patients in the trial. This study is open and currently enrolling patients. Clinical trial information: NCT02631447.
An In Vitro Model for Identifying Cardiac Side Effects of Anesthetics
Authors: Chang Alex C. Y. , Chang Andrew C. H. , Nicin Luka , Weber Gerhard J. , Holbrook Colin , Davies M. Frances , Blau Helen M. , Bertaccini Edward J.
Published: September 2018

The understanding of anesthetic side effects on the heart has been hindered by the lack of sophisticated clinical models. Using micropatterned human-induced pluripotent stem cell–derived cardiomyocytes, we obtained cardiac muscle depressant profiles for propofol, etomidate, and our newly identified anesthetic compound KSEB01-S2. Propofol was the strongest depressant among the 3 compounds tested, exhibiting the largest decrease in contraction velocity, depression rate, and beating frequency. Interestingly, KSEB01-S2 behaved similarly to etomidate, suggesting a better cardiac safety profile. Our results provide a proof-of-concept for using human-induced pluripotent stem cell–derived cardiomyocytes as an in vitro platform for future drug design.
Physiological responses of ionotropic histamine receptors, PxHCLA and PxHCLB, to neurotransmitter candidates in a butterfly, Papilio xuthus
Authors: Akashi Hiroshi D. , Chen Pei-Ju , Akiyama Tokiho , Terai Yohey , Wakakuwa Motohiro , Takayama Yasunori , Tominaga Makoto , Arikawa Kentaro
Published: September 2018

Histamine is the only known neurotransmitter released by arthropod photoreceptors. Synaptic transmission from photoreceptors to second order neurons is mediated by the activation of histamine-gated chloride channels (HCLs). These histaminergic synapses have been assumed to be conserved among insect visual systems. However, our understanding of the channels in question has thus far been based on studies in flies. In the butterfly Papilio xuthus, we have identified two candidate histamine-gated chloride channels, PxHCLA and PxHCLB, and studied their physiological properties using a whole-cell patch-clamp technique. We studied the responses of channels expressed in cultured cells to histamine as well as to other neurotransmitter candidates, namely GABA, tyramine, serotonin, D-/L- glutamate, and glycine. We found that histamine and GABA activated both PxHCLA and PxHCLB, while the other molecules did not. The sensitivity to histamine and GABA was consistently higher in PxHCLB than in PxHCLA. Interestingly, simultaneous application of histamine and GABA activated both PxHCLA and PxHCLB more strongly than either neurotansmitter individually; histamine and GABA may have synergistic effects on PxHCLs in the regions where they colocalize. Our results suggest that the physiological properties of the histamine receptors are basically conserved among insects, but that the response to GABA differs between butterflies and flies, implying variation in early visual processing among species.
Head-mounted sensors reveal visual attention of free-flying homing pigeons
Authors: Kano Fumihiro , Walker James , Sasaki Takao , Biro Dora
Published: September 2018

Gaze behavior offers valuable insights into attention and cognition. However, technological limitations have prevented the examination of animals' gaze behavior in natural, information-rich contexts; for example, during navigation through complex environments. Therefore, we developed a lightweight custom-made logger equipped with an inertial measurement unit (IMU) and GPS to simultaneously track the head movements and flight trajectories of free-flying homing pigeons. Pigeons have a limited range of eye movement, and their eye moves in coordination with their head in a saccadic manner (similar to primate eye saccades). This allows head movement to act as a proxy for visual scanning behavior. Our IMU sensor recorded the 3D movement of the birds' heads in high resolution, allowing us to reliably detect distinct saccade signals. The birds moved their head far more than necessary for maneuvering flight, suggesting that they actively scanned the environment. This movement was predominantly horizontal (yaw) and sideways (roll), allowing them to scan the environment with their lateral visual field. They decreased their head movement when they flew solo over prominent landmarks (major roads and a railway line) and also when they flew in pairs (especially when flying side by side, with the partner maintained in their lateral visual field). Thus, a decrease in head movement indicates a change in birds' focus of attention. We conclude that pigeons use their head gaze in a task-related manner and that tracking flying birds' head movement is a promising method for examining their visual attention during natural tasks.
Dietary antioxidants, but not courtship effort, affect oxidative balance in the testes and muscles of crickets
Authors: Simmons Leigh W. , Lovegrove Maxine , Lymbery Samuel J.
Published: September 2018

Recent interest has focused on the role of reactive oxygen species (ROS) as universal constraints in life-history evolution. Empirical studies have examined the oxidative costs of reproduction for females, with little work conducted on males. The male germline is thought to be particularly susceptible to oxidative damage because the testes, and sperm themselves, can be prolific producers of ROS. We tested the hypothesis that protection of the male germline from oxidative damage represents a cost of reproduction for males. We fed male crickets, Teleogryllus oceanicus, with one of two experimental diets in which we manipulated the availability of dietary antioxidants and induced variation in their expenditure on courtship effort by manipulating access to females. We measured the total antioxidant capacity, levels of ROS production and the amount of oxidative damage to proteins in both testis and thoracic muscle tissues. Dietary antioxidants contributed to positive oxidative balance in both tissue types. Although testes had greater antioxidant defences than muscle tissue, they also produced considerably higher levels of ROS and sustained higher levels of oxidative damage. Courtship effort had no impact on any measure of oxidative balance. Our data confirm that the male germline is especially susceptible to oxidative stress and that dietary antioxidants can alleviate this oxidative cost of reproduction.
A Theoretical Study on Redox Potential and pKa of [2Fe-2S] Cluster Model from Iron-Sulfur Proteins
Authors: Kurniawan Isman , Kawaguchi Kazutomo , Shoji Mitsuo , Matsui Toru , Shigeta Yasuteru , Nagao Hidemi
Published: September 2018

Iron-sulfur proteins are essential in several biological processes, such as electron transfers in photosystems and respiratory chains. The range of redox potentials of these proteins are so wide that many substrates can interact with them. Thus, the redox potentials of the iron-sulfur proteins are crucial to facilitate the process. This study aims to investigate the redox potential of iron-sulfur proteins with [2Fe-2S] core by using two typical exchange-correlation functionals in density functional theory (DFT), i.e., B3LYP and M06, with and without the diffuse function. Since it involves transition metals, several types of spin approximation were also explored, such as high spin (HS), low spin (LS), approximated spin projection (AP), and J coupling parameter (JC) methods. We found that the diffuse function contributes to improving the accuracy. We also found that M06 functional produced more accurate results than B3LYP. The best result is obtained for AP UM06/6-31++G(d,p) with the absolute error of 0.01 V.
Offshoring and Labor Markets
Authors: Hummels David , Munch Jakob R. , Xiang Chong
Published: September 2018

In this paper, we survey the recent empirical literature on the effects of offshoring on wage, employment, and displacement. We start with an overview of the measurement of offshoring, organizing our discussion around the three key elements of offshoring: that it involves intermediate inputs for production (versus final goods for consumption); that it involves imported inputs (versus domestically produced ones); and that the inputs involved could have been produced internally within the same firm. We then briefly discuss the theories of offshoring and survey the literature that examines the wage effects of offshoring: the wave of studies using industry-level data; the wave using firm-level data; the wave using worker-level data; and the wave using matched worker-firm data. For each wave, we highlight the identification strategies used, critically assess its strengths and weaknesses, discuss its connections with theory, and draw out potential policy implications of its findings. Finally, we survey the literature that examines how offshoring affects employment and displacement. We highlight the recent development of a novel cohort-based approach that is specifically designed to address selection with displacement, and capable of identifying the overall effects of offshoring, including wage, displacement, and all other types of transitions. (JEL F23, J24, J31, J63, L24, M55)
Inverted repeat structures are associated with essential and highly expressed genes on C. elegans autosome distal arms
Authors: Reich Daniel P. , Bass Brenda L.
Published: September 2018

Complementary sequences in cellular transcripts base-pair to form double-stranded RNA (dsRNA) structures. Because transposon-derived repeats often give rise to self-complementary sequences, dsRNA structures are prevalent in eukaryotic genomes, typically occurring in gene introns and untranslated regions (UTRs). However, the regulatory impact of double-stranded structures within genes is not fully understood. We used three independent methods to define loci in Caenorhabditis elegans predicted to form dsRNA and correlated these structures with patterns of gene expression, gene essentiality, and genome organization. As previously observed, dsRNA loci are enriched on distal arms of C. elegans autosomes, where genes typically show less conservation and lower overall expression. In contrast, we find that dsRNAs are associated with essential genes on autosome arms, and dsRNA-associated genes exhibit higher-than-expected expression and histone modification patterns associated with transcriptional elongation. Genes with significant repetitive sequence content are also highly expressed, and, thus, observed gene expression trends may relate either to dsRNA structures or to repeat content. Our results raise the possibility that as-yet-undescribed mechanisms promote expression of loci that produce dsRNAs, despite their well-characterized roles in gene silencing.
ОЦЕНКА ЭФФЕКТИВНОСТИ РАБОТЫ ПРЕДПРИЯТИЯ ПО РЕМОНТУ МАШИН И ОБОРУДОВАНИЯ НА ОСНОВЕ СТАТИСТИЧЕСКОГО АНАЛИЗА ИЗНОСА ДЕТАЛЕЙ
Authors: Lazhauninkas Julia Vladimirovna
Published: September 2018

В связи с экономическим кризисом, наблюдающимся во всех отраслях народного хозяйства, а также с недостаточным финансированием, в настоящее время происходит значительный спад производства сельскохозяйственной техники. Сельскохозяйственные предприятия не могут приобретать новую технику. В связи с этим возникает необходимость грамотного планирования применения имеющейся техники так, чтобы ее можно было использовать максимально эффективно, с минимальными затратами на ремонт и техническое обслуживание.В экономической эффективности работы сельскохозяйственного предприятия немаловажную роль играет надежность техники, поэтому ее прогнозирование различными средствами позволяет снизить общие затраты. Правильная эксплуатация и своевременный ремонт машин и оборудования позволяет повысить работоспособность, тем самым, снижая простои техники.В настоящее время наблюдается довольно обостренная ситуация с проблемой надежности машин. Это, прежде всего, связано с все более возрастающей сложностью конструкции современных машин и механизмов, их многодетальностью, интенсификацией рабочих процессов, тяжелыми условиями эксплуатации. Эффективность решения задачи замены или ремонта деталей, а следовательно, и вопрос об экономической эффективности работы ремонтного предприятия, находится в прямой зависимости от степени научно-методического сопровождения соответствующих мероприятий, одним из которых является процесс оценки износа деталей.Цель исследования: исследовать эффективность работы предприятия по ремонту машин и оборудования на основе статистического анализа износа шейки под шарикоподшипник 208 вала первичной коробки передач МТЗ-82, установить что в данном случае более эффективно – ремонт или замена рассматриваемой детали.Методы исследования: методы статистического анализа.Результаты: Получены наиболее информативные параметры, отражающие износ шейки под шарикоподшипник 208 вала первичной коробки передач МТЗ-82. На основе проведенного анализа установлено, что, с экономической точки зрения, своевременное техническое обслуживание и текущий ремонт рассматриваемой детали является более эффективным, чем ее замена на новую.Область применения результатов: результаты исследования могут быть использованы при оценке экономической эффективности работы предприятия по ремонту машин и оборудования.
МЕТОДИКА ОЦЕНКИ ВОЕННО-ЭКОНОМИЧЕСКОГО ЭФФЕКТА, ПОЛУЧАЕМОГО ПРИ ВНЕДРЕНИИ ТЕХНОЛОГИЙ «ИНДУСТРИИ 4.0» В СФЕРЕ ВЕЩЕВОГО ОБЕСПЕЧЕНИЯ ВОЕННЫХ ПОТРЕБИТЕЛЕЙ
Authors: Krasovitov Roman Aleksandrovich
Published: September 2018

В современных условиях происходит быстрое развитие инструментов повышения эффективности логистических систем, основанных на сочетании гибкого сотрудничества между элементами, входящими в их состав, широкого использования средств автоматизации и информатизации и адаптации конечного продукта к специфическим запросам конкретного заказчика (т. н. технологий «Индустрии 4.0»). Сложность оценки военно-экономического эффекта от применения инструментария «Индустрии 4.0» в сфере вещевого обеспечения войск (сил) связана с тем, что факторы (составляющие) этого эффекта, во-первых, имеют разную природу (что усложняет их непосредственное сопоставление), во-вторых, зачастую трудно измеримы, из-за чего оценка совокупного военно-экономического эффекта неизбежно будет носить приблизительный характер.Цель работы: построение методики оценки военно-экономического эффекта от применения «Индустрии 4.0» в сфере вещевого обеспечения военных потребителей.Методы: общенаучные методы анализа и синтез, метод экономико-математического моделирования.Результаты: на основе выявления факторов, обуславливающих возникновение военно-экономического эффекта, построена методика оценки военно-экономического эффекта от применения инструментов «Индустрии 4.0» в сфере вещевого обеспечения войск (сил).