bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I, open-label, first-time-in-patient dose escalation and expansion study to assess the safety, tolerability, and pharmacokinetics of nanoparticle encapsulated Aurora B kinase inhibitor AZD2811 in patients with advanced solid tumours.
Authors: Burris Howard A. , Wang Judy Sing-Zan , Johnson Melissa Lynne , Falchook Gerald Steven , Jones Suzanne Fields , Strickland Donald K , Greenlees Carol , Brugger Wolfram , Charlton Julie , Pease Elizabeth , MacDonald Alexander
Published: September 2018

TPS2608

Background: Aurora kinase B performs key roles in the regulation of the cell cycle and represents a potential target for anticancer therapy. AZD2811, formerly designated AZD1152 hydroxy-quinazoline pyrazole anilide (AZD1152 hQPA), is a potent and selective inhibitor of Aurora B kinase activity and has been incorporated into a polymer nanoparticle carrier for intravenous (IV) administration. The phosphate pro-drug of AZD2811, known as AZD1152 (barasertib), reached Phase II of clinical development as a continuous IV infusion. While promising efficacy was seen with barasertib in elderly acute myeloid leukaemia (AML) patients ( Kantarjian HG et al., Cancer 2013;119:2611-19), continuous intravenous drug delivery precluded subsequent development in this disease setting and there were limited clinical responses in solid tumour patients due to dose-limiting myelotoxicity. AZD2811 nanoparticle has been designed to overcome these issues. Methods: Patients with relapsed advanced solid malignancies with no standard treatments are eligible for the part A dose escalation. Primary endpoint is to determine the maximum tolerated dose of AZD2811 nanoparticle using a 3+3 design. Patients with refractory/relapsed small cell lung cancer (SCLC) will be eligible for the part B expansion, where the safety, PK and anti-tumour activity of AZD2811 nanoparticle will be assessed as monotherapy and in combination with chemotherapy. Study enrolment is ongoing. Clinical trial information: NCT02579226.
Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: A phase I exposure escalation study.
Authors: Mammatas Lemonitsa Hillegonda , Zandvliet Anthe S. , Rovithi Maria , Honeywell Richard , Swart Eleonora , Peters Godefridus J. , Menke Catharina Wilhelmina , Verheul Henk M.W.
Published: September 2018

TPS2620

Background: Sorafenib is currently prescribed at a standard fixed dose of 400 mg twice daily in a continuous schedule. Increased exposure to sorafenib is associated with improved outcome. However, further increase in the dose of this continuous schedule is precluded due to toxicity. A high-dose, pulsatile schedule may result in increased sorafenib exposure while maintaining acceptable toxicity and has demonstrated promising preclinical antitumor activity.1 Sorafenib plasma concentrations present with large interpatient variability. As drug effectivity is largely dependent on AUC exposure, personalized dose titration based on the sorafenib plasma AUC0-12h of an individual patient seems more suitable than a standard fixed dose. In this phase I trial, a high-dose, weekly schedule of sorafenib is being studied, using exposure escalation cohorts based on a target AUC0-12h, instead of conventional dose escalation cohorts. Methods: Adult patients are included with locally advanced or metastatic solid tumors for whom no standard therapy exists. High-dose sorafenib is administered once a week. Pharmacokinetic monitoring is performed during the first 3 weeks of treatment in each patient to evaluate if the target plasma sorafenib AUC0-12h of the cohort is reached and sorafenib dose is adjusted accordingly. Cohorts consist of 3-6 patients per exposure level, starting with target AUC0-12h 25-50 mg x h/L, analogous to the continuous schedule. The target AUC0-12h is increased in subsequent cohorts until exposure limiting toxicity occurs. Main objectives are to assess safety and establish the maximum tolerated plasma AUC0-12h of high-dose, pulsatile sorafenib. At this dose level 10 extra patients will be included. Tumor biopsies are required in all patients of this expansion cohort to study antitumor effects and for direct comparison of plasma and intratumor sorafenib concentrations. Furthermore, a simplified method will be developed for measurement of plasma sorafenib exposure using dried blood spot sampling at 1-2 time points. Nine patients have already been included. Reference: 1Wang X. et al. J Transl Med 2011;9:220. Clinical trial information: NCT02636426.
The Molecular Screening and Therapeutics (MoST) Program: A precision medicine framework for biomarker-driven signal-seeking clinical studies for rare cancers.
Authors: Hess Dominique , Sebastian Lucille T , Sjoquist Katrin Marie , Lee Chee Khoon , Hague Wendy , Miller Danielle , Cowley Mark , Qiu Min Ru , Fox Stephen B. , Joshua Anthony M. , Simes John , Thomas David Morgan
Published: September 2018

TPS2621

Background: Precision medicine aims to link molecular targets in tumors to cognate therapies and has the potential to yield new treatments for cancer patients with unmet clinical need. With the accelerating pace of discovery and genomic capacity, innovative approaches are needed to translate molecular opportunities into clinical care. The MoST program tests a novel paradigm for evaluation of biomarker-driven treatment of patients with advanced cancer. The key elements of the design are a molecular screening platform to identify ‘actionable’ variants and an overarching protocol for multiple, parallel, signal-seeking clinical substudies. Methods: 1000 patients with advanced solid cancer of any histologic type, having failed all standard therapies will undergo tumor molecular profiling on archival tissue with a 393-gene panel and other molecular assays. Eligibility for biomarker-driven substudies of targeted treatments is based on tumor variants assessed by a Molecular Tumor Board. A novel framework design allows expedited addition of substudies, with ≥12 open-label, single-arm, signal-seeking substudies planned. The primary objective is to identify signals of clinical activity, as measured by objective tumor response or the ratio of time-to-progression on study treatment over the preceding period. Cohorts of 16 patients will be recruited to each substudy. Substudies with ≥3/16 responding patients will be considered sufficiently interesting to investigate further.As of Feb 2017, 65 patients have been screened, and 8 recruited to 2 open sub-studies: CDK4/6 inhibitor (palbociclib) for Rb pathway defects; CTLA-4 plus PD-L1 checkpoint inhibitors (durvalumab + tremelimumab) for patients with no actionable mutations. Additional substudies under development include: PARP plus PD-L1 inhibitors (olaparib + durvalumab) for HR DNA repair defects; SMO inhibitor (vismodegib) for Hh pathway defects. The modular signal-seeking trial design will be evaluated and is intended to expedite testing of biomarker-based therapies for rare cancers. Clinical trial information: ACTRN12616000908437; ACTRN12616000931471; ACTRN12616001019493.
A NKG2D-based CAR-T therapy in a multinational phase I dose escalation and expansion study targeting multiple solid and hematologic tumor types.
Authors: Verma Bikash , Aftimos Philippe Georges , Awada Ahmad , Machiels Jean-Pascal H. , Brayer Jason B. , Sallman David A , Kerre Tessa , Odunsi Kunle , Lonez Caroline , Gilham David Edward , Lehmann Frederic
Published: September 2018

TPS3093

Background: Chimeric Antigen Receptor (CAR)-T therapy has potentially serious limitations related to target antigen loss, toxicity due to pre-conditioning regimen, and lack of activity in many tumor types. To overcome these limitations, we have developed a novel CAR-T, called NKR-2, incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain. When expressed in T-cells, the naturally-expressed DAP10 provides co-stimulatory signals to NKR-2 to produce cytokines and selectively target tumor cells upon recognition of up to 8 different stress-induced NKG2D ligands expressed in many solid and hematologic malignancies. In preclinical studies, NKR-2 demonstrated long-term anti-tumor activity towards a breadth of tumor indications, in the absence of pre-conditioning, whilst simultaneously targeting tumor cells and cells from the local tumor neo-vasculature and suppressive immune environment. In our recently completed First-in-Human Phase 1 study (NCT02203825) in hematologic cancers, a single administration of autologous NKR-2 was safe with initial signs of clinical benefit. Methods: Exploiting the multiple ligand targeting capability and unique mode of action of NKR-2, the THINK trial (THerapeutic Immunotherapy with NKR-2) is an open-label Phase I study that will assess the safety and clinical activity of multiple infusion NKR-2 treatment (every 2 weeks x 3 infusions) in relapse/refractory patients with metastatic or locally advanced CRC, urothelial carcinoma, TNBC, pancreatic cancer, recurrent epithelial ovarian and fallopian tube carcinoma, AML/MDS and MM, post standard treatment. The study contains two consecutive segments. The dose escalation segment will enroll 18 patients in two separate hematologic and solid malignancy arms, and will evaluate 3 dose levels of NKR-2 (3x108, 1x109 and 3x109 per injection) following a 3+3 design. The expansion segment will then enroll 96 additional patients in 7 separate cohorts for each indication with 3 steps of statistical analysis (overall futility, cohort futility and final evaluation). The study is open for recruitment in both EU and US. Clinical trial information: NCT03018405.
Two phase I/II open label clinical trials evaluating the safety and efficacy of autologous T cells expressing enhanced TCRs specific for NY-ESO-1 or MAGE-A10 in subjects with stage IIIb or stage IV non-small cell lung cancer (NCT02588612/NCT02592577).
Authors: Creelan Ben C. , Gainor Justin F. , Govindan Ramaswamy , Hardy Nancy M. , Heymach John , Mudad Raja , Reckamp Karen L. , Bardwell William , Holdich Tom , Bartlett-Pandite Arundathy N. , Amado Rafael G.
Published: September 2018

TPS3096

Background: Non-small cell lung cancer (NSCLC) accounts for 84% of lung cancer. Survival has recently been impacted by molecularly targeted therapies and checkpoint inhibitors (CPI), and the promising CPI results implicate a role for the immune system in NSCLC. 10-40% of NSCLC express NY-ESO-1 or MAGE-A10 cancer/testis antigens. These studies will evaluate the safety and antitumor activity of genetically engineered affinity enhanced TCRs (NY-ESO-1c259T or MAGE-A10c796T) directed towards a NYESO-1 or MAGE-A10 derived peptides complexed with HLA-A*02. In addition, correlative studies to evaluate persistence, phenotype, functionality of engineered T cells, mechanisms of resistance and antigen spreading will be performed. Methods: Patients (pt) are screened (NCT02636855) to identify those who have the relevant HLA-A*02 alleles and NY-ESO-1 or MAGE-A10 tumor expression. For entry into either treatment protocol, pt must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness. Following apheresis, T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259T or MAGE-A10c795 TCR, and infused into the pt following lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The NY-ESO-1c259T study is a 10 pt study utilizing a dose of 1-6 x 109 transduced T cells. The MAGE-A10c796T first-in-human study is a modified 3+3 design in up to 28 pt with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T cells, with staggered treatments to allow for safety review; dose escalation will be guided by the DLT observed and by safety review committee guidance. Response to treatment will be assessed by RECIST v1.1 at weeks 4, 8, 16, 24, every 3 months (for 2 yr) and every 6 months until disease progression. Clinical trial information: NCT02588612/NCT02592577.
A phase 1b study to evaluate TAK-659 in combination with nivolumab in patients (pts) with advanced solid tumors.
Authors: Juric Dejan , Faucette Stephanie , Wang Ling , Niu Huifeng , Kannan Karuppiah , Stumpo Kate , Rong Yuanxin , Shou Yaping , Nemunaitis John J.
Published: September 2018

TPS3104

Background: TAK-659 is an investigational, reversible, potent dual inhibitor of SYK and FLT-3. In ongoing early-phase studies (NCT02000934; NCT02323113), TAK-659 demonstrated an acceptable pharmacokinetic and safety profile, with evidence of preliminary activity in pts with DLBCL, follicular lymphoma, CLL, and AML (Kaplan et al. Blood 2016;128:624/2834). In preclinical studies, TAK-659 in combination with nivolumab, an anti-PD-1 checkpoint inhibitor, resulted in loss of myeloid suppressor cells (MDSCs), increased T-cell activation, and complete tumor growth suppression (Kannan et al. Eur J Cancer 2016;69:S92). This first-in-human combination study will investigate the efficacy and safety of TAK-659 and nivolumab in pts with advanced solid tumors. Methods: This open-label, multicenter, phase 1b study (NCT02834247) will include dose-escalation and expansion phases. Pts with advanced solid tumors who have failed ≥1 prior lines of therapy and have no effective therapeutic options available by investigator assessment will be eligible for the dose-escalation phase. Pts will receive oral TAK-659 at doses of 60–100 mg QD in a standard 3+3 schema, plus nivolumab 3 mg IV on days 1 and 15 of 28-day cycles. The expansion phase at the recommended phase 2 dose (RP2D) will include 3 cohorts of pts with relapsed/refractory metastatic triple-negative breast cancer, locally advanced/metastatic NSCLC, or locally advanced/metastatic head and neck squamous cell carcinoma (n = 30 response-evaluable pts in each cohort; 24 naïve, 6 relapsed/refractory to prior anti-PD-1/PD-L1 therapy). Ten pts in each cohort will receive 2 weeks of single-agent TAK-659 before starting combination therapy; the other 20 pts will receive combination therapy throughout. The primary endpoints are maximum tolerated dose/RP2D (dose-escalation phase) and overall response rate by investigator per RECIST v1.1 (expansion phase). Secondary endpoints include adverse events, disease control rate, duration of response, progression-free survival, overall survival, and TAK-659 pharmacokinetics. There are currently 7 pts enrolled; recruitment to the 100 mg dose-escalation cohort is ongoing. Clinical trial information: NCT02834247.
Integrate II: A randomised phase 3 double-blind placebo-controlled study of regorafenib in refractory advanced gastro-oesophageal cancer (AGOC)—An international study organized by the Australasian Gastrointestinal Trials Group (AGITG).
Authors: Sjoquist Katrin Marie , Pavlakis Nick , Martin Andrew James , Tsobanis Eric , Yip Sonia , Bang Yung-Jue , Alcindor Thierry , O'Callaghan Christopher J. , Shitara Kohei , Bekaii-Saab Tanios S. , Grothey Axel , Chen Li-Tzong , Simes John , Zalcberg John Raymond , Goldstein David
Published: September 2018

TPS4136

Background: AGOC has a poor prognosis with no established standard treatment following failure of chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT). INTEGRATE (phase 2) demonstrated REG was highly effective in prolonging PFS across a range of AGOC pts, with a positive OS trend. Regional differences were found in magnitude of effect, but REG was effective in all regions/subgroups. The phase 3 INTEGRATE II will explore whether REG is effective in prolonging survival in patients overall, and in the Asian sub-population. Methods: International (Australia/New Zealand (NHMRC CTC); Canada (CCTG), Korea, Japan, Taiwan, USA (ACCRU)) randomised phase III, double-blind, placebo-controlled trial with 2:1 (REG:placebo)(PBO) randomisation and stratification by: Location of tumour, Geographic region, prior VEGF inhibitors. Eligible patients (histologically confirmed AGOC), with evaluable metastatic or locally advanced disease refractory to, or relapsed following second line CT, will receive best supportive care plus 160mg REG or matched placebo orally on days 1-21 of each 28 day cycle until disease progression or prohibitive adverse events. Primary endpoint is OS. Secondary endpoints: PFS, response rate, quality of life, safety, identification of prognostic/predictive biomarkers for study endpoints, and REG PK across geographical regions. 350 patients (50% from Asia) randomized in a 2:1 ratio will provide 90% power to detect a hazard ratio (HR) for OS of 0.67 with a 2-sided α of 0.05 assuming PBO median survival is 4.5 mos. The sample size accommodates 2 interim analyses undertaken at 1/3 and 2/3 of required events. As of January 2017, 12 of 28 planned ANZ sites are open, with 4 patients enrolled. Regulatory approval has been received for 12 Canadian sites, and 12 Korean sites. Korean recruitment is expected to commence in February 2017. Regulatory submissions are pending in Taiwan, Japan, and the USA. Clinical trial information: NCT02773524.
A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Powles Thomas , Fizazi Karim , Gillessen Silke , Drake Charles G. , Rathkopf Dana E. , Narayanan Sujata , Green Marjorie C. , Mecke Almut , Schiff Christina , Sweeney Christopher
Published: September 2018

TPS5090

Background: In the past decade, several therapies have been approved for patients (pts) with mCRPC, including the androgen receptor (AR) antagonist enzalutamide (enza) and the androgen synthesis inhibitor abiraterone acetate (abi). Despite these advances, most pts experience disease progression and there are inadequate data to guide the sequencing of agents to optimize outcomes. Pts with mCRPC who progress on enza have increased circulating PD-L1/PD-L2–positive dendritic cells compared with enza-naive pts or pts who are still responding to treatment (Bishop et al. Oncotarget. 2014). In two recent studies, PSA and radiographic responses were observed in mCRPC pts treated with a PD-L1/PD-1 pathway inhibitor with or without enza (Graff et al. Oncotarget. 2016; Hansen et al. Ann Oncol. 2016). Atezolizumab (atezo) is an anti–PD-L1 monoclonal antibody that inhibits the interaction between PD-L1 and its receptors, PD-1 and B7.1, enhancing T-cell responses and improving anti-tumor activity. Taken together, this suggests that the combination of atezo and enza may provide an effective treatment option for mCRPC pts. Methods: A Phase III randomized, multicenter, clinical trial (NCT03016312) is being conducted to evaluate the efficacy and safety of atezo with enza compared with enza alone in mCRPC pts who have received prior abi treatment and have progressed on, are ineligible for, or have refused a taxane regimen. Eligibility criteria include mCRPC or locally advanced, incurable CRPC and ECOG PS 0-1. Exclusion criteria include CNS metastasis, autoimmune disease, history of seizures, prior immunotherapy and prior treatment with enza or any other newer AR antagonists. Pts will be randomized 1:1 to receive atezo 1200 mg q3w and enza 160 mg qd or enza alone. The primary endpoint is OS, and secondary endpoints include PSA response rate, rPFS, ORR and safety. Exploratory biomarkers associated with responses to atezo and enza will be evaluated in tumor tissue collected at baseline and progression. Approximately 550 pts will be enrolled at 150 sites globally. Clinical trial information: NCT03016312.
ARASENS phase 3 trial of ODM-201 in men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Smith Matthew Raymond , Saad Fred , Hussain Maha , Sternberg Cora N. , Fizazi Karim , Crawford E. David , Yamada Karin Sayuri , Kappeler Christian , Kuss Iris , Tombal Bertrand F.
Published: September 2018

TPS5092

Background: Androgen deprivation therapy (ADT) ± docetaxel is recommended first-line therapy for mHSPC, but most patients progress to castration-resistant PC (CRPC). BAY-1841788 (ODM-201) is an investigational oral androgen receptor (AR) antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. In preclinical studies, ODM-201 and its main circulating metabolite are active also in known AR mutants (eg, W742L, F877L), and have been found to have negligible blood-brain barrier penetration. In the phase 1 ARAFOR and phase 1/2 ARADES trials, ODM-201 had antitumor activity and was well tolerated in men with mCRPC (Massard et al. Eur Urol. 2016;69:834‒840; Fizazi et al. Lancet Oncol. 2014;15:975‒985). Given this promising activity in mCRPC, the ARASENS trial is evaluating ODM-201 plus standard ADT + docetaxel in men with metastatic disease (mHSPC). Methods: This international, randomized, double-blind, placebo-controlled, phase 3 trial (NCT02799602) is being conducted in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to either ODM-201 600 mg twice daily (2×300 mg tablets) orally with food or placebo, both with ADT + docetaxel (6 cycles after randomization), and stratified by extent of disease and alkaline phosphatase levels. Key inclusion criteria are histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation anti-androgen therapy ≤12 weeks before randomization, and Eastern Cooperative Oncology Group performance status 0 or 1. The primary objective is to show superior overall survival with ODM-201 vs placebo, both with ADT + docetaxel. Secondary end points include time to CRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event-free survival (SSE-FS), time to first SSE, initiation of opioid use, pain progression, and worsening of physical symptoms, all measured at 12-week intervals. Safety will be assessed by adverse events. The trial is open for enrollment; first patient first visit was in November 2016 and > 10 sites are open for recruitment and enrolling patients. Clinical trial information: NCT02799602.
Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer: The ENGOT-EN2/DGCG trial.
Authors: Mirza Mansoor Raza , Lundgren Caroline , Kridelka Frederic , Ferrero Annamaria , Greggi Stefano , Christensen Rene dePont , Santaballa Ana , Soliman Pamela T. , Levy Tally , Sehouli Jalid , Cibula David , Auranen Annika , Lund Bente , Roennengart Eva , Amant Frederic
Published: September 2018

TPS5613

Background: Patients with medium and high-risk stage I and II endometrial cancers (EC) have, despite radical surgery, a high risk for progression. Adjuvant brachytherapy or EBRT is the traditional therapy for many decades although without impacting on survival. Several studies have failed to demonstrate superiority of adjuvant chemotherapy in unselected population with a high number of low-risk patients. It is of utmost importance to demonstrate efficacy of adjuvant combination chemotherapy in a randomized trial comparing to no further treatment in the medium and high-risk node negative stage I and stage II patients. Methods: The primary objective of this trial is to evaluate the effect on overall survival of carboplatin-paclitaxel combination chemotherapy against no further systemic treatment. Key eligibility criteria include: histologically confirmed EC, stage I grade 3 endometrioid adenocarcinoma or stage II endometrioid adenocarcinoma or stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, carcinosarcoma or undifferentiated carcinoma); prior surgery with pelvic lymphadenectomy or sentinel lymph node biopsy. Patients may receive vaginal brachytherapy in both arms. 240 patients are randomized to receive six courses of adjuvant carboplatin (AUC5) and paclitaxel (175mg/m2) combination on day one every 21 days or no further treatment (1:1 randomization). Primary endpoint is overall survival of endometrioid subgroup. Secondary endpoints include overall survival of whole study population, disease specific survival, progression-free survival, toxicity, compliance, Quality of Life (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24), rate of isolated pelvic or distant relapses, as well as mixed relapses. Trial is enrolling patients. The following cooperative groups are participating: DGCG (DK), NSGO (DK, FIN, SWE), BGOG (BEL), MaNGO (ITA), MITO (ITA), GEICO (SPA), NOGGO (GER), CEEGOG (Czech), ISGO (ISR) & MDACC (USA). Clinical trial information: NCT01244789.
A randomized, double-blind phase II study of pembrolizumab versus placebo in patients with head and neck cancers at high risk for recurrence or low-volume residual disease: The PATHWay Study.
Authors: Bauml Joshua , Karrison Theodore , Vokes Everett E. , Cohen Roger B. , De Souza Jonas A. , Aggarwal Charu , Saloura Vassiliki , Agrawal Nishant , Saba Nabil F. , Langer Corey J. , Seiwert Tanguy Y.
Published: September 2018

TPS6095

Background: Head and neck squamous cell carcinoma (HNSCC) is a major medical problem worldwide. While some patients may be cured with a combination of surgery, radiation, and systemic therapies, a significant percentage of patients will have recurrent and incurable disease. Despite our epidemiologic understanding of which patients are likely to recur, there are no consolidative therapies that have been shown to improve outcomes in this high-risk population. Pembrolizumab is a PD-1 inhibitor that has shown significant single agent activity in recurrent/metastatic HNSCC after treatment with other systemic therapies. While drug development of pembrolizumab is ongoing in Phase III studies in the 2nd and 1stline recurrent/metastatic disease settings, the ultimately the biggest potential impact based on patient volume and survival will potentially be in the curative intent setting. This randomized study is intended to explore the incorporation of pembrolizumab into the treatment of patients with locally advanced HNSCC at high risk for recurrence. Methods: Eligible patients must have HNSCC, completed therapy with definitive intent, and have an estimated risk of recurrence ≥40-50% (including tumors with extensive lymphadenopathy, extracervical lymphadenopathy, indeterminate residual local or distant mass after treatment, non-responders to induction chemotherapy, incomplete definitive therapy, receipt of salvage therapies, or oligometastatic disease treated definitively). Patients will be randomized to 1 year of either pembrolizumab 200 mg or placebo, administered intravenously day 1 of each 3-week cycle. The primary hypothesis of the study is that the addition of pembrolizumab will improve the 2-year progression-free survival (PFS) rate, compared to placebo. A sample size of 90 (45 patients per treatment arm, assuming 10% loss of follow up in N = 100 patient trial) will achieve 92.7% power at alpha = 0.10 (one-sided) to detect a difference between 50% and 72.5% PFS at 2 years. Approximately 51 events are required to detect such a difference. Patient screening and enrollment are expected to begin spring 2017.
A phase Ib study of atezolizumab (atezo) alone or in combination with lenalidomide or pomalidomide and/or daratumumab in patients (pts) with multiple myeloma (MM).
Authors: Cho Hearn J. , Cole Craig , Martin Thomas G. , Zonder Jeffrey A. , Fay Joseph W. , Vij Ravi , Byon John CH , Stewart A. Keith , Dhodapkar Madhav V.
Published: September 2018

TPS8053

Background: The advent of proteasome inhibitors and immunomodulatory drugs (IMiDs) have significantly improved outcomes in MM, and the first monoclonal antibodies for MM have been recently approved (daratumumab, elotuzumab). Despite novel therapies and improved disease management, MM is still considered incurable and most pts relapse, confirming the need for additional treatment options. MM cells express PD-L1, with higher levels observed after relapse and with advanced disease. Additionally, PD-L1–expressing immune cells in the microenvironment promote MM cell survival and potential immune escape. However, anti–PD-1 monotherapy did not result in objective responses in the MM cohort of a Ph I study, suggesting that MM pts need combination therapy. Daratumumab has activity as a single agent, as well as in combination with IMiDs plus dexamethasone and bortezomib plus dexamethasone in R/R MM. Immunomodulatory activity for daratumumab has also been reported. Thus, disruption of the PD-L1/PD-1 pathway may be additive or synergistic. The safety and efficacy of atezo (anti–PD-L1) alone or with lenalidomide or pomalidomide and/or daratumumab will be evaluated in a Ph Ib study of MM pts. NCT02431208. Methods: R/R MM pts with ≤ 3 prior therapies will be enrolled in Cohorts A (atezo), B (atezo + lenalidomide), D (atezo + daratumumab) and E (atezo + daratumumab + lenalidomide); MM pts with measurable disease after ASCT (Cohort C: atezo) or ≥ 3 prior therapies (Cohort F: atezo + daratumumab + pomalidomide) will also be enrolled. Cohorts B, D, E and F include a safety run-in (D) or dose escalation phase (B, E, F) and an expansion. Lenalidomide and pomalidomide will be dose escalated and the MTD evaluated in expansion phases. Atezo will be given at 1200 mg IV (A, B, C) or 840 mg IV (D, E, F); pts will get daratumumab at 16 mg/kg IV (D, E, F). All pts will be ECOG PS ≤ 2. Primary endpoints are ORR and the RP2D of lenalidomide and pomalidomide with atezo and daratumumab and the RP2D of lenalidomide with atezo. DOR and PFS are secondary endpoints; safety, PK and the relationship between biomarkers and other endpoints, including efficacy, will be assessed. Pts will be enrolled at 19 US sites. Clinical trial information: NCT02431208.
Durvalumab (DURVA) plus daratumumab (DARA) in patients (pts) with relapsed and refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Bensinger William , Weisel Katja C. , Boyd Kevin , Ramasamy Karthik , Gonzalez Esther , Favre-Kontula Linda , Peluso Teresa , Sternas Lars Axel , Di Casoli Carl , Zaki Mohamed H. , Facon Thierry
Published: September 2018

TPS8054

Background: DARA, a monoclonal antibody (mAb) against CD38, is approved for RRMM. Combination treatment (Tx) with DARA + DURVA, a mAb against programmed death ligand-1 (PD-L1), may enhance host anti-MM immunity and response. DARA and PD-L1 mAbs have each demonstrated clinical activity in combination with pomalidomide (POM) + low-dose dexamethasone (LoDEX) in MM. Thus, the phase 2 MEDI4736-MM-003 trial is evaluating DURVA + DARA in RRMM, and, in an exploratory analysis, the addition of POM + LoDEX to DARA + DURVA either upon progressive disease (PD) with DARA + DURVA or as up-front Tx will be assessed. Methods: ≈ 144 pts with RRMM are being enrolled. Pts with measurable MM who received ≥ 3 prior anti-MM Txs, including a protease inhibitor and an immunomodulatory agent, or are double-refractory to these 2 agents will be included. Exclusion criteria include allogeneic stem cell transplant (SCT), autologous SCT ≤ 12 weeks, and prior DARA or other CD38 antibody therapies. Primary endpoints are overall response rate (ORR) and safety. Secondary endpoints are time to response, duration of response, progression-free survival, and pharmacokinetics. The study includes a 3 + 3 safety run-in phase to confirm the tolerability of the recommended phase 2 doses (RP2Ds) of DURVA and DARA. Dose-limiting toxicities will be evaluated during the first Tx cycle. Safety and efficacy will be assessed by a Simon 2-stage design (Table). POM + LoDEX may be added to DARA + DURVA in pts who received ≥ 2 cycles of DARA + DURVA and had confirmed PD. Based on preliminary safety and efficacy, the 4-drug regimen may be explored as up-front Tx. Tx with either the 2- or 4-drug regimens will continue until PD or unacceptable toxicity. Pts treated with POM will be followed for second primary malignancies every 6 mos until the end of the trial. To date, 6 pts have enrolled in the run-in phase. Clinical trial information: NCT02807454. [Table: see text]
A phase III, randomized, open-label study of isatuximab (SAR650984) plus pomalidomide (Pom) and dexamethasone (Dex) versus Pom and Dex in relapsed/refractory multiple myeloma.
Authors: Richardson Paul G. , Attal Michel , San Miguel Jesus , Campana Frank , Le-Guennec Solenn , Hui Ai-Min , Risse Marie-Laure , Anderson Kenneth Carl
Published: September 2018

TPS8057

Background: Treatment for refractory or relapsed and refractory multiple myeloma (MM) remains an unmet need. Isatuximab (ISA), an anti-CD38 monoclonal antibody with multiple mechanisms of tumor killing, has shown efficacy and an acceptable tolerability profile in Phase 1/2 studies in patients with refractory or relapsed and refractory MM (RRMM) (Richter et al. ASCO 2016; Vij et al. ASCO 2016). Methods: This Phase III, prospective, multicenter, randomized, open-label study (NCT02990338; ICARIA-MM) is being conducted to evaluate the clinical benefit of ISA in combination with Pom and low-dose Dex (Pom/Dex) versus Pom/Dex for the treatment of adult patients with RRMM and demonstrated disease progression within 60 days of the last therapy, and who have received at least 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) alone or in combination. Patients will be randomly assigned in a 1:1 ratio to either ISA (10 mg/kg IV on Days 1, 8, 15, and 22 in the 1st cycle; Days 1 and 15 in subsequent cycles) plus Pom (4 mg on Days 1–21) and Dex (40 mg for patients < 75 years of age and 20 mg for patients ≥75 years of age, on Days 1, 8, 15, and 22) or Pom and Dex. Treatment cycles will be 28 days each. Patients will continue therapy until disease progression, occurrence of unacceptable adverse events (AEs), or their decision to discontinue the study, whichever comes first. The primary endpoint is progression-free survival (PFS), i.e. time from randomization to progressive disease or death from any cause. Response will be determined by IMWG criteria (2016). Key secondary endpoints include overall response rate and overall survival (OS). Safety evaluations include treatment-emergent AEs/serious AEs (including infusion-associated reactions), laboratory parameters, vital signs and assessment of physical examination. Statistical analyses will be conducted according to a pre-specified plan; approximately 300 patients (150 in each arm) are expected to be enrolled in this study. The first patient was recruited in January 2017. Study funding: Sanofi. Clinical trial information: NCT02990338.
A phase II, noncomparative, open label, multicentre, study of AZD9291 in patients with locally advanced or metastatic EGFR mutated “T790M undetectable or unknown” non-small cell lung cancer (stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).
Authors: Soto Parra Hector J. , Noto Laura , Galetta Domenico , Ferraú Francesco , Gebbia Vittorio , Tassone Pierfrancesco , Verderame Francesco , Aiello Marco M. , Latteri Fiorenza , Novello Silvia
Published: September 2018

TPS9107

Background: Osimertinib (OSI), is an oral, potent, irreversible inhibitor of both epidermal growth factor receptor (EGFR) sensitizing and resistance mutations (T790M) indicated for the treatment of pts with advanced EGFR T790M mutation-positive NSCLC. In the AURA study, OSI was associated with an ORR of 21% (13/61) among all patients with T790M negative mutation. Response rate broken down by immediate versus no immediate prior EGFR TKI was 11% (4/36 pts) versus 36% (9/25) respectively. This better activity with deferred OSI, drug able to inhibit also the EGFR sensitizing mutations, could be explained by a selection of sensitive tumor cells during chemotherapy (re-challenge strategy). Aim of the current study is prospective evaluate the efficacy of OSI in EGFR mutated, T790M “undetectable or unknown” patients as third-line therapy after a first-line EGFR TKI and a subsequent chemotherapy. Methods: OSIRIS study is a prospective single-arm, phase 2, open label, italian multicenter study. T790M “undetectable or unknown" is defined by the following conditions: inconclusive/negative tumor test result for T790M at the time of disease progression or medical inaccessible/contraindications/declined tumor biopsy or insufficient tumor tissue for testing. Pts are treated with OSI 80 mg once daily until disease progression or unacceptable toxicity. The single-arm design is appropriate, as there is no accepted standard therapy for these pts after chemotherapy. The primary endpoint is ORR according to RECIST version 1.1. The null hypothesis that the true response rate is 9% will be tested against a one-sided alternative. In the first stage, 32 pts will be accrued. If there are 3 or fewer responses in these 32 pts, the study will be stopped. Otherwise, 49 additional pts will be accrued for a total of 81. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 19%. Secondary endpoints are PFS, OS and safety. Exploratory: mutational analysis of a panel of genes involved in resistance to EGFR-TKIs is planned. Clinical trial information: 2016-002555-17.
СВЯЗЬ АМБИЦИОЗНОСТИ И ПРОФЕССИОНАЛЬНОЙ НАПРАВЛЕННОСТИ ЮНОШЕЙ И ДЕВУШЕК
Authors: Valiullina Gulnara Gaisaevna , Romanova Olga Vyacheslavovna
Published: September 2018

Цель. Статья посвящена проблеме осознанного выбора профессии в юношеском возрасте, что является актуальным в связи с возрастанием потребностей общества в более квалифицированных специалистах. Предметом исследования является связь амбициозности личности и профессиональной направленности в юношеском возрасте. Авторы ставят целью выявить особенности влияния амбициозности на профессиональную направленность юношей и девушек.Метод или методология работы. Исследование проводилось с использованием диагностических методик: «Определение профессиональных склонностей» Л. Йовайши, «Исследование самооценки личности» С.А. Будасси, «Диагностика мотивации достижения» А. Мехрабиан, «Диагностика стратегий поведенческой активности в стрессовых условиях» Л.И. Вассермана и Н.В. Гуменюка. Использованы математико-статистические методы обработки данных, включающие в себя вычисление описательных статистик, критерия Колмогорова-Смирнова для одной выборки, критерия Стьюдента для независимых выборок, критерия Манна-Уитни, ранговую корреляцию Спирмена. Все расчеты выполнялись с помощью компьютерной программы IBM SPSS Statistics 21.Результаты. Проведенное эмпирическое исследование позволяет констатировать наличие связи амбициозности и профессиональной направленности юношей и девушек. Между юношами и девушками в показателях профессиональной направленности выявлены достоверные различия. Юноши отдают предпочтение сфере технических интересов, умственного труда, материальных интересов, а девушки – сфере искусства и работе с людьми. В группе юношей были установлены значимые связи между показателями амбициозности и профессиональной направленностью на сферу технических интересов. В группе девушек были установлены значимые связи между показателями амбициозности и направленностью на сферу работы с людьми. Амбициозные юноши и девушки характеризуются осознанностью своих профессиональных склонностей и стремлением добиться намеченных целей в профессиональном плане.Область применения результатов. Результаты исследования могут быть применены в практике психологического консультирования при профориентировании, открывают новые возможности для разработки профориентационных программ.
Government Relations: theory, strategies and national practices. Complete guide
Authors: Мухаев Рашид , Muhaev Rashid
Published: September 2018

This publication is one of the first textbooks on the subject "Theory and practice of Government Relations" and a complete guide to GR, the content of which is based on a comparative analysis of the theories, strategies and technologies of communication of interested groups with state and municipal authorities in different countries. The status and nature of GR as a science and art are revealed, methodological and applied issues of designing strategies and practices for converting functional groups ' requests, including business structures, into a mechanism for making and implementing political decisions are revealed.
When using the strategy of comparative analysis, communicative practices of interaction of interested groups and authorities in the United States are considered. in the countries of Western Europe, Japan and China, the advantages and disadvantages of national models of GR are revealed, strategies and technologies of positioning of interest groups in Russia, the mechanism of promotion of corporate requests in the public sphere are shown.
Corresponds to the Federal state educational standard of higher education of the last generation.
The legislation of different countries on GR-practices is relevant as of July 1, 2018.
For students of higher educational institutions studying in the areas of "Advertising and PR", "State and municipal administration", "political Science".
EFEKTIVITAS PENAGIHAN PAJAK DENGAN SURAT TEGURAN DAN SURAT PAKSA TERHADAP PENERIMAAN PAJAK PADA KANTOR PELAYANAN PAJAK PRATAMA SLEMAN
Authors: Wahyuningtyas Fika , Ariesanti Alia
Published: September 2018

Tax collection by using a letter of reprimand and forced letter is an effort to increase the effectiveness of tax revenue that purpose as the country's development. This research method aims to determine the level of effectiveness of the tax collection and forced letter warning letter. The research method uses descriptive method of analysis, methods based on existing data, and then draw conclusions. This study uses secondary limit the period 2011-2012. Analysis using ratio analysis to calculate the effectiveness of tax collection by using related variables that include the amount of the tax billing plan and the amount of tax revenue. The results showed that the effectiveness of tax collection with a letter of reprimand and a letter run ineffectively enforced, so expect authorize agencies in collecting tax debts can be optimized, see realize taxes are still very small
FAKTOR-FAKTOR YANG MEMPENGARUHI PENERIMAAN OPINI AUDIT GOING CONCERN
Authors: Vernando Andreas , Yuniarto Arif Sapta
Published: September 2018

Auditor in doing a audit is responsible to evaluate whether auditee gets problem in maintainig its existence. One of its indication is auditee gets the financial distress. Therefore, if doubting a capable auditee in maintainig its existence, Auditor commonly brings out going concern audit opinion for giving signalement to investor so that investor does not make the mistake in interpretating the economic decision. The researchs with topics going-concern audit opinion have been comprehensive enough. this is seen of many variables gone into researchs model. However, researchs with topics going-concern audit opinion must be continously renewed. This is caused economy condition that is always dinamic having to research continously. This research purposed to obtain the empirical evidence of factors influencing acceptance going-concern audit opinion. This research focussed for researching manufacture sector which was listed at Indonesian stock exchange from periods 2009 until 2012 used as research sample. the result of purposive sampling method was obtained as many as 39 manufacture companies which fill up sample criterion and the tests of hypotesis use logistic regression analysis. The results of hypotesis test showed that tenure influenced acceptance of going-concern audit opinion
ANALISIS AKUNTANSI PERTANGGUNGJAWABAN DALAM PENILAIAN KINERJA PADA KOPERASI PEGAWAI REPUBLIK INDONESIA SEMPULUR, KABUPATEN MAGELANG
Authors: Arif Didik Muhamad , Imron Moch
Published: September 2018

The purpose of this study is to find the application of accounting accountability in performance evaluation of based on the regulation of health assessment cooperativesf. Aspects assessment health cooperatives that used in the capital are aspects, management aspects of, aspects growth and independence. The data used in research it will be reports on the results of members meetings annual from 2012 until the year of 2014.metoda used an author in this research is method descriptive. The research results show that the implementation of accounting accountability in performance evaluation of based on the regulation cooperatives and smes minister no.14 2009 on the capital 2012 categorized good criteria healthy weight value 35,91 34,28-42,85, 2013 categorized pretty good with criteria pretty healthy value 30,78bobot 25,71-34,28dan in 2014 categorized good criteria sehatnilai 34,28 34,28-42,85 weight.Performance evaluation of management aspects of in 2012 and last until 2014 categorized good criteria healthy weight value 34,98 34,28-42,85.While assessment performance aspects independence and growth in 2012 categorized not very nice criteria were very unhealthy value 6.24 0-8,57 weight.In 2013 and 2014 categorized less than good criteria unhealthy value 23,54 with weights 17,14-25,71.
IVF: A case of ‘less is more’?
Authors: Windsor Sophie
Published: September 2018

Despite the sucess of IVF over the past 40 years, funding cuts have encouraged couples to travel abroad for treatment. But, Sophie Windsor asks, could they return with more than they intended?
Immunosuppression following organ transplantation. Part 1: mechanisms and immunosuppressive agents
Authors: Cajanding Ruff
Published: September 2018

Solid organ transplantation has revolutionised medical care by providing a definitive cure for a wide spectrum of end-stage medical conditions. This treatment, however, does not come without complications and poses the risks of rejection, life-threatening infection, malignancies and recurrent organ failure, with significant impacts on patient outcomes. One of the major challenges involved in optimising post-transplant outcomes is managing the immune system's response to the transplanted graft and preventing organ rejection. This is mainly accomplished through the use of immunosuppressant agents, which have become a mainstay of treatment for a majority of post-transplant patients. This article, the first of two parts, discusses the concept of immunosuppression and its importance in the care of patients who have received an organ transplant. It focuses on the pathophysiologic mechanisms involved in transplant rejection and discusses the pharmacologic aspects of immunosuppression and its implications for patient care.
How nurse leadership has evolved
Authors: Nobbs Alan
Published: September 2018

Alan Nobbs, Senior Programme Lead, NHS Leadership Academy, concludes a series of blogs on his nursing career by exploring changes in leadership development and stresses that the nursing voice is as crucial as ever
End of year report cards from NHS Resolution and the CQC
Authors: Tingle John
Published: September 2018

John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses two reports looking at the beginning and end stages of patient safety failures
Using Thyronorm for hyperthyroidism treatment
Authors: Taylor Samantha
Published: September 2018

Hyperthyroidism is the most commonly diagnosed feline endocrinopathy, diagnosed frequently in older cats. The incidence of hyperthyroidism has increased since its first description in 1979, and cats are now more often diagnosed at an early stage. Diagnosis and treatment can be challenging, particularly in cats with comorbidities, and recent research suggests avoiding hypothyroidism is important to negate negative effects on long-term survival. While radioactive iodine is the treatment of choice in uncomplicated hyperthyroid cats, it is not appropriate in all circumstances, and medical treatment can be very useful.