bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of durvalumab (Medi 4736) in advanced endometrial cancer: PHAEDRA.
Authors: Antill Yoland Catherine , Stockler Martin R. , Kok Peey Sei , Robledo Kristy Pamela , Gillies Kim , Stark John , Yip Sonia , Mileshkin Linda R. ,   Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Published: September 2018

TPS5614 Background: Advanced endometrial cancer (EC) progressing after 1 or more lines of chemotherapy is an area of unmet need with objective tumour response rates to subsequent lines of chemotherapy of ≤20%. DNA mismatch repair (MMR) deficiency, seen in approximately 15% of EC, is associated with a high mutational load and in addition, up to 90% of ECs are reported to have PDL1/ PD1 expressions. These factors make immune check point inhibition an ideal target for treatment. Methods: DESIGN: Multicentre phase 2 trial in two cohorts. ELIGIBILITY: Advanced, unresectable endometrial cancer that is either MMR-proficient and progressing after 1-3 lines of chemotherapy, or MMR-deficient and progressing after 0-3 lines of chemotherapy. ENDPOINTS: Objective tumour response rate (OTRR) according to iRECIST (primary) and RECIST 1.1, disease control rates at 16 and 24 weeks, progression free survival, overall survival, duration of OTR and DC, adverse events, health related quality of life. Tertiary correlative objectives: Associations between immunologic (including PD-L1), DNA mismatch repair (MMR) and other genetic characteristics with clinical outcomes; and family history of cancer and referral to familial cancer services. INTERVENTION: Durvalumab 1500 mg intravenously every 28 days until disease progression or prohibitive toxicity. STATISTICS: Total of 70 participants in two cohorts (35 each) will have 90% power to distinguish a difference in observed OTRR of ≥20% versus ≤5% (uninteresting rate) using Simon’s 2-stage minimax design with 10% type 1 error rate and allowing 10% ineligibility and missing data. Durvalumab will be considered worthy of pursuit if 4 or more OTR are observed in the first 32 participants in each cohort (OTRR ≥12.5%). BIOSPECIMENS: Tumour tissue and serial bloods (5 time points) will be collected for translational research. PHAEDRA is an investigator-initiated, cooperative-group trial led by ANZGOG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney. Australian New Zealand Clinical Trials Registry: Clinical trial information: ACTRN12617000106336.
CORALLEEN: A phase 2 clinical trial of chemotherapy or letrozole plus ribociclib as neoadjuvant treatment for postmenopausal patients with luminal B/HER2-negative breast cancer.
Authors: Gavilá Joaquín , Saura Cristina , Oliveira Mafalda , Ortega Vanesa , Lopez Rafael , Ciruelos Eva M. , Gonzalez Xavier , Zaragoza Katrin , Pelaez Rivas Alexandra , de La Pena Lorena , Prat Aleix 
Published: September 2018

TPS594 Background: Dysregulation of cyclin D-CDK4/6-Rb pathway is associated with endocrine resistance in hormone receptor–positive (HR+) breast cancer. Recently, a CDK4/6 inhibitor has shown unprecedented efficacy in metastatic disease, leading to its regulatory approval. Several others are currently in clinical development for the management of HR+ breast cancer in the early and advanced settings. However, it is vital to gain insights into the molecular and biological effects of this class of agents and could identify patients who can benefit the most, delaying or avoiding the use of chemotherapy.The neoadjuvant setting provides an ideal scenario to carry out these investigations. Hence, we propose to conduct an exploratory study to evaluate the biological effects and the efficacy of ribociclib in patients with primary luminal B tumors.We hypothesize that the combination of ribociclib plus letrozole may offer clinical benefit in the preoperative setting. Methods: This is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable HR+/HER2-negative Luminal B breast cancer designed to evaluate the clinical benefit of ribociclib plus letrozole. Eligibility includes stage I-III operable breast cancer, Luminal B by PAM50, ECOG 0-1. They will be randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy: four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens will be collected for molecular characterization and evaluation of response (decrease in Ki67, change to ROR low disease) The primary endpoint is the rate of Residual Cancer Burden (RCB) per MD Anderson Cancer Center procedures. A rate of RCB 0 and 1 score at surgery, with a rank between 20% to 25% with 47 evaluable patients by group of treatment will offer a precision between 11.5% and 12.4%, respectively (95%CI). Ninety-four patients will be enrolled in 20 sites across Spain.
Phase II study of durvalumab (anti-PD-L1 antibody) in combination with R-CHOP or lenalidomide plus R-CHOP in previously untreated, high-risk diffuse large B-cell lymphoma.
Authors: Nowakowski Grzegorz S. , Kalakonda Nagesh , Truemper Lorenz , Everaus Hele , Fustier Pierre , Jaeger Jonathan , Manzke Oliver , Jäger Ulrich ,   And the MEDI4736-DLBCL-001 Trial Investigators
Published: September 2018

TPS7573 Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells and may provide an effective target for enhancing anticancer immune response. In DLBCL, high PD-L1 expression has been identified as a negative prognostic factor for overall survival. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and preliminary preclinical and clinical activity support the study of durvalumab in high-risk DLBCL subtypes. The primary study objective is to explore the clinical activity of durvalumab with R-CHOP in non-activated B-cell–like (non-ABC) and durvalumab with lenalidomide + R-CHOP (R2-CHOP) in ABC previously untreated DLBCL; secondary objectives are to evaluate safety and identify biomarkers predictive of clinical response. Methods: This is a phase II, two-arm, open-label, global, multicenter study of durvalumab combinations in patients with previously untreated, high-risk DLBCL (MEDI4736-DLBCL-001; EUDRA CT 2015-005173-20; NCT03003520). High risk was defined as Ann Arbor stage III/IV or II with bulky disease (≥7.0 cm), along with intermediate-high/high IPI ≥3 or NCCN-IPI ≥4; patients must also have CD20+ DLBCL, ECOG PS 0-2, and no prior antilymphoma therapy. All patients receive durvalumab + R-CHOP21 in induction cycle 1 simultaneous to cell-of-origin (COO) analysis by gene expression profiling with NanoString technology. Beginning with cycle 2, Arm A (non-ABC) receives durvalumab 1125 mg IV on day 1 with 6 or 8 cycles of R-CHOP21; Arm B (ABC) receives the same durvalumab + R-CHOP21 doses with oral lenalidomide 15 mg/day on days 1-14. Both arms receive durvalumab consolidation 1500 mg IV on day 1 q28d for ≤12 months from induction cycle 1, day 1. The primary endpoint is 2-y progression-free survival (PFS); secondary endpoints include clinical response to treatment in biomarker-defined subpopulations (tumor and peripheral blood) and safety as assessed per NCI CTCAE v4.03 criteria. Exploratory endpoints include PFS at 12 mo, complete response, and PK/PD. Recruitment is ongoing, with a target enrollment of 120 patients. Clinical trial information: NCT03003520.
CheckMate 602: An open-label, randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide and dexamethasone in relapsed/refractory multiple myeloma.
Authors: Lonial Sagar , Richardson Paul G. , Reece Donna Ellen , Mohamed Hesham , Shelat Suresh , San Miguel Jesus 
Published: September 2018

TPS8052 Background: Multiple myeloma (MM) cells may evade immune surveillance by suppressing immune responses through the PD-1 pathway, via upregulation of PD-L1.1Nivolumab (nivo), a PD-1 immune checkpoint inhibitor that blocks PD-L1 interaction and disrupts MM-mediated PD-1 signaling, demonstrated modest activity as monotherapy in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in a phase 1b study.2 Pomalidomide, an immunomodulatory drug (IMiD), may sensitize MM cells to PD-1 blockade, and has shown efficacy with dexamethasone (Pd) for RRMM. Elotuzumab (elo), an anti-SLAMF7 monoclonal antibody, directly activates natural killer cells and facilitates antibody-dependent cell-mediated cytotoxicity. Preclinical work suggests PD-1 blockade may enhance elo efficacy3; thus nivo + Pd + elo may increase clinical benefit. Methods: CheckMate 602 (NCT02726581) is a phase 3, open-label, randomized study of efficacy and safety of nivo + Pd (N-Pd) vs Pd in pts with RRMM. Nivo combined with elo + Pd (NE-Pd) will be evaluated in an exploratory arm. Eligible pts must have measurable MM after ≥2 prior lines of therapy (LoTs) that included an IMiD and proteasome inhibitor, each for ≥2 consecutive cycles, alone or combined, and be refractory to their last LoT. Pts with prior elo are eligible. A planned 406 pts will be randomized 3:3:1 to N-Pd, Pd and NE-Pd, stratified by LoT (2 vs 3+) and International Staging System disease stage (I–II vs III). Pts in the Pd arm may cross over to the NE-Pd arm at disease progression. Pts are enrolled at 119 sites in 13 countries. Coprimary endpoints (N-Pd and Pd arms): objective response rate (ORR) and progression-free survival (PFS), assessed by an independent review committee. Secondary endpoints (N-Pd and Pd arms): time to response, duration of response, investigator-assessed ORR and PFS. Exploratory endpoints include ORR and PFS (NE-Pd arm), and safety/tolerability and minimal residual disease status (all arms). 1. Liu et al. Blood 2007;110:296–304 2. Lesokhin et al. JCO 2016;34:2698–704 3. Bezman et al. Haematologica 2016;101:161–2 [S450] Study support: BMS. Writing support: A Gill, Caudex, funded by BMS. Clinical trial information: NCT02726581.
Detect T790M in cell free tumor DNA of Chinese advanced non-small cell lung cancer adenocarcinoma patients by different platforms and evaluate clinical outcomes of T790M positive patients with osimertinib monotherapy.
Authors: Liang Zhiyong , Cheng Ying , Chen Yuan , Liu Weiping , Lu You , Wang Jie , Wu Gang , Ying Jian-Ming , Zhang Xu-Chao , Wu Yi-Long 
Published: September 2018

TPS9104 Background: EGFR T790M mutation occurs in approximately 50-60% of non-small cell lung cancer adenocarcinoma (NSCLC) patients with acquired EGFR-TKI resistance, based on tumor re-biopsies using an invasive clinical procedure. Recently, Cell free tumor DNA (ctDNA) has emerged as a specific and sensitive blood-based biomarker and studies have demonstrated ctDNA as a feasible and minimally invasive alternative to tissue biopsy. Data on different technology platforms used for EGFR T790M detection in blood in China is limited. We aim to compare the methods currently available in hospital practise, including cobas EGFR Mutation Test (Roche Molecular Systems), super-ARMS, digital PCR and NGS, to compare each platform and clinically validate each as companion diagnostic to osimertinib. Methods: This is an open-label, multi-center study in 250 locally advanced or metastatic NSCLC patients with documented EGFR sensitizing mutation and progression on previous EGFR-TKI. T790M mutation in plasma ctDNA will be tested by four methods: cobas, super-ARMS, digital PCR and NGS in order to evaluate the concordance, sensitivity and specificity of T790M testing in plasma between the cobas test and the other platforms. T790M positive patients by any of the four platforms will receive osimertinib treatment (administered orally as one 80 mg tablet once a day in ASTRIS study, NCT02474355) and the clinical outcomes (PFS, ORR, OS) will be followed. Patients will continue to receive osimertinib until disease progression (PD), as assessed by investigators. Digital PCR and NGS will be used to monitor the molecular evolution of T790M and C797S in plasma from NSCLC patients during osimertinib treatment. NGS will also be used to explore acquired resistance mechanisms before osimertinib treatment and after PD. 23 of planned 250 patients have been enrolled in the study as of January 2017. Clinical trial information: NCT02997501.
METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC.
Authors: Mehta Minesh P. , Gondi Vinai , Brown Paul D. 
Published: September 2018

TPS9106 Background: Tumor Treating Fields (TTFields) are non-invasive regional anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly-diagnosed glioblastoma patients. Methods: 270 patients with 1-10 brain metastases (BM) from NSCLC will be randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2nd cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2st cerebral progression. Objectives: To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Endpoints: Time to 1st cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Main eligibility criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, no electronic implantable devices in the brain. Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day will be applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. Clinical trial information: NCT02831959.
Phase 1 study to evaluate safety and efficacy of ipilimumab + nivolumab + external beam radiotherapy in patients with metastatic melanoma.
Authors: Postow Michael Andrew , Knox Susan Jane , McCabe Danielle , Macri Mary J. , Schwarzenberger Paul , Ricciardi Toni , Ryan Aileen , Venhaus Ralph Rudolph , Barker Christopher Andrew 
Published: September 2018

TPS9591 Background: Immunotherapy (IMT) with checkpoint blocking antibodies has led to progress in metastatic melanoma with 3 FDA-approved drugs, including the combination of ipilimumab (IPI), a CTLA-4 antibody, and nivolumab (NIVO), a PD-1 antibody. Although radiotherapy (RT) is primarily used as local palliative therapy in metastatic melanoma, it also possibly affects systemic antitumor immunity. Preclinical data suggest RT alters the tumor microenvironment and renders tumor cells more susceptible to immunologically-mediated disease regression. These preclinical immunologic effects of RT have been shown to vary by RT dose and fractionation. We are now conducting the first clinical trial in patients to evaluate the triple combination of IPI + NIVO + RT using 2 different dose/fractionation schemes of RT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02659540) evaluates safety, efficacy, and immunologic effects of IPI + NIVO + RT in 18 patients with unresectable stage IV melanoma. Patients must have 1 melanoma metastasis that can be safely irradiated for palliative purposes and at least 1 measurable lesion that will not be irradiated. Patients receive concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks (Q3W) x 4, followed by NIVO monotherapy (240 mg Q2W), with RT initiated between the first and second doses of IPI + NIVO. In Cohort A, the irradiated metastasis receives a conventionally fractionated low dose of 30 Gy in 10 fractions of 3 Gy each over 2 weeks. If ≤7 of 9 patients (78%) in Cohort A have Grade 3/4 drug- or radiation-related adverse events, safety is deemed acceptable and Cohort B enrollment opens. In Cohort B, the irradiated metastasis receives a hypofractionated high dose of 27 Gy in 3 fractions of 9 Gy each over 2 weeks. The primary endpoint is safety. Secondary endpoints are objective response rate and disease control rate by RECIST and immune-related RECIST measured at Weeks 12 and 18, duration of response, progression-free survival, and overall survival. Exploratory endpoints include correlative studies of immunological effects. Enrollment opened on 05 Aug 2016. As of 31 Dec 2016, 4 patients are enrolled in Cohort A; enrollment is ongoing. Clinical trial information: NCT02659540.
NCI 9922: Phase 2 study of ibrutinib in treatment-refractory distant metastatic cutaneous melanoma (DMCM).
Authors: Moschos Stergios J. , Eroglu Zeynep , Gaughan Elizabeth Mary , Medina Theresa Michelle , Wang Peng , Dees Elizabeth Claire , Cartee Leanne , Arrowood Christy , Carson Craig , Thomas Nancy E , Ollila David W. , Nikolaishvilli-Feinberg Nana , Ivy S. Percy , Harris Pamela Jo , Hurwitz Herbert 
Published: September 2018

TPS9592 Background: We have previously shown that the IL-2 inducible kinase (ITK) is highly expressed in primary melanomas compared with nevi due to promoter hypomethylation (Conway PCMR 2011). We have also shown using 2-color immunofluorescence (2CIF) that ITK protein expression is increased even more in metastatic compared to primary melanomas (S100+) and that molecular targeting (shRNA) or pharmacologic inhibition of ITK (BI 10N) in various melanoma cell lines, various melanoma xenografts and an immunocompetent melanoma mouse model suppresses cell proliferation and retards tumor growth without inducing cell death (Carson CCR 2015). We have also shown by intracellular stain of peripheral blood mononuclear cells (PBMC) that ITK is expressed in PBMC obtained from patients (pts) treated with MAPK or CTLA-4 inhibitors. Other groups have shown that ITK and BTK are expressed in Th2 cells, myeloid-derived suppressor cells, and tumor-associated macrophages. We have also shown that ibrutinib suppresses proliferation of various melanoma cell lines in low nM concentrations depending on tumoral expression of ITK. We hypothesize that targeting DMCM with ibrutinib alone will induce antitumor responses and/or prolong survival if DMCM expresses high levels of melanoma-associated ITK by 2CIF (S100/ITK). Methods: This is an open-label, single-arm, multicenter, phase II study of DMCM refractory to or ineligible for PD-1 and MAPK inhibitors. Ibrutinib will be dosed at 840 mg p.o. qd. The null hypothesis is that an ineffective drug will confer a 5% response rate (RR) and 18% 6-month PFS (6m PFS), whereas ibrutinib will confer > = 20% RR and > = 35% 6m PFS (KEYNOTE-002). This trial accrues in two stages; if either the RR and/or 6m PFS endpoint are met after 18 patients, then 14 additional pts will be accrued for a total of 32. The Simon’s design will reject the null hypothesis if > = 4 responses are observed or > = 9 pts have PFS better than 6 months out of 32 patients. All pts are required to have baseline tumor tissue available for analysis of ITK expression by 2CIF. Immune monitoring will be performed on PBMC collected at baseline and various time points during treatment. Trial is currently recruiting pts (NCT02581930). Clinical trial information: NCT02581930.
CHARACTERIZATION OF PLUTONIUM DISTRIBUTION IN THO2–PUO2 MIXED OXIDES BY ELECTRON PROBE MICROANALYSIS
Authors: Woods Dawn , Saoudi Mouna , Mayhew Clinton , Ham-Su Rosaura 
Published: September 2018

Thoria–plutonia (ThO2–PuO2) pellets with a nominal composition of 9.0 wt% PuO2 were prepared using a fabrication route similar to an industrial process for production of urania–plutonia (UO2–PuO2) mixed oxide fuel. The green fuel pellets were separated into 2 batches and the sintering of each batch was carried out under a reducing atmosphere at 1820 °C or 1750 °C. The distribution of plutonium (Pu) in the sintered pellets was investigated by electron probe microanalysis using X-ray mapping and quantitative point analyses. The results show that the pellet samples consist of Pu-rich agglomerates with Pu content close to that of the mastermix blend and a thorium (Th)-rich matrix. The matrix and the Pu-rich agglomerates are separated by a transition zone with Pu content varying from practically nil to the Pu content of the Pu-rich agglomerates. X-ray maps taken from random regions of the centre of the pellets show different sizes of Pu-rich agglomerates irregularly dispersed in the Th-rich matrix. Image analysis of the Pu X-ray maps indicate that the average diameter of the Pu-rich agglomerates of the material sintered at 1820 °C and 1750 °C were 68 μm and 161 μm, respectively.
A system under pressure
Authors: Smith Ed , Dasan Sunil 
Published: September 2018

Activity levels within emergency medicine, and the pressures experienced by individual clinicians working within the specialty, continue to increase year on year. In 2016–17 there were 18 691 546 attendances at UK emergency departments. Attendance numbers continue to increase annually, patients are becoming older and more unwell, departments are more crowded and as a result, emergency care standard performance figures are deteriorating. This article describes the impact of this pressure on the staff working within the emergency department and begins to explore the potential for the development of sustainability within the existing and future workforce.
Restoration of uterine redox-balance by methanolic extract of Camellia sinensis in arsenicated rats
Authors: Dey Arindam , Chattopadhyay Sandip , Jana Suryashis , Giri Mukul Kumar , Khatun Shamima , Dash Moumita , Perveen Hasina , Maity Moulima 
Published: September 2018

Arsenic, an environmental and industrial pollutant causes female reproductive disturbances and female infertility. Several researchers found that the use of Camellia sinensis (CS) (green tea) is effective as an alternative therapeutic strategy in the management of several health ailments. This study explores the role of CS extract against arsenic-induced rat uterine tissue damage. Methanolic extract of CS (10 mg/kg BW) was tested concomitantly in arsenic-treated (10 mg/kg BW) rats for a duration of two-oestrous cycle length (8 days). CS effectively attenuated arsenic-induced antioxidantdepletion and necrosis in uterine tissue. Rats treated with sodium arsenite showed significantlyreduced activities of enzymatic antioxidants like superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in uterine tissue as evidenced by the results of spectrophotometric and electrozymographic analysis. Co-administration of CS significantly reversed the above oxidative stress markers in uterine tissue along with the histopathological changes in ovarian and uterine tissue. Moreover, an increase in the level of transcription factor NF-κB in the uterine tissue in association with reduced serum levels of vitamin B12 and folic acid were mitigated in arsenic fed rats following CS co-administration.