bluuebunny/crossref_metadata_2025_split huggingface dataset:
JAVELIN head and neck 100: A phase 3 trial of avelumab in combination with chemoradiotherapy (CRT) vs CRT for 1st-line treatment of locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Lee Nancy Y. , Ferris Robert L. , Beck J. Thaddeus , Harrington Kevin , Haddad Robert I. , Bourhis Jean , Tahara Makoto , Geraldes Margarida , Nuyten Dimitry S. A. , Goldberg Zelanna , Cohen Ezra E.W. 
Published: September 2018

TPS6093 Background: Cisplatin + radiotherapy is a standard-of-care treatment for patients (pts) with LA SCCHN. Combining avelumab (fully human IgG1 anti–PD-L1 antibody) and CRT may synergistically activate multiple immune-mediated mechanisms to effect a robust and durable antitumor response and improve long-term disease control. Methods: JAVELIN Head and Neck 100 (NCT02952586) is a global, multicenter, randomized, double-blind, phase 3 trial of avelumab + cisplatin-based CRT vs placebo + CRT as 1st-line treatment for pts with LA SCCHN. The primary objective is to demonstrate superiority of avelumab + CRT in prolonging progression-free survival (PFS) vs CRT alone. Eligible pts have LA SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx; HPV− or non-oropharyngeal HPV+ disease of stage III, IVa, or IVb; or HPV+ oropharyngeal disease T4, N2c, or N3. Pts must be candidates for cisplatin-based CRT. Other eligibility criteria include ECOG PS ≤1 and no prior systemic treatment for advanced disease. Approximately 640 pts will be randomized 1:1 to receive avelumab 10 mg/kg (1-hour IV) + CRT (intensity-modulated RT [70 Gy/35 fractions] + cisplatin 100 mg/m2 [x3]) or placebo + CRT. There will be 3 treatment phases: lead-in (single dose of avelumab or placebo), CRT (concurrent avelumab or placebo + CRT for 7 weeks), and maintenance (avelumab or placebo Q2W for 12 months). The rationale for this design is to induce an immune response during lead-in and CRT phases, followed by maintenance treatment to prolong and support immune memory development. The primary endpoint is PFS per modified RECIST v1.1. Secondary efficacy endpoints include overall survival, objective response, locoregional failure, distant metastatic failure, and duration of response. Other endpoints include safety, pharmacokinetics, immunogenicity, pt-reported outcomes, and biomarker assessments. Treatment will continue for 12 months following initiation of the maintenance phase or until progressive disease, unacceptable toxicity, or any other protocol-defined criterion for withdrawal occurs. Enrollment in this phase 3 trial began in November 2016. Clinical trial information: NCT02952586.
An open-label, randomized phase III study of gilteritinib versus salvage chemotherapy in relapsed or refractory FLT3 mutation-positive acute myeloid leukemia.
Authors: Perl Alexander E. , Cortes Jorge E. , Strickland Stephen Anthony , Ritchie Ellen K. , Neubauer Andreas , Martinelli Giovanni , Naoe Tomoki , Pigneux Arnaud , Rousselot Philippe H. , Röllig Christoph , Baer Maria R. , Larson Richard A. , James Angela Joubert , Chen Caroline , Shu Lei , Hasabou Nahla , Bahceci Erkut 
Published: September 2018

TPS7067 Background: FLT3 mutations occur in 30% of patients with acute myeloid leukemia (AML), most often as internal tandem duplications (FLT3-ITD) or point mutations at codon D835. FLT3-ITDs are associated with high relapse rates, short remission duration, and poor overall survival (OS); FLT3-D835 can confer resistance to other tyrosine kinase inhibitors (TKIs). Gilteritinib is a highly selective FLT3/AXL TKI with activity against both FLT3-ITD and FLT3-D835 mutations. A recent phase 1/2 study of gilteritinib (20–450 mg/d) in relapsed/refractory (R/R) AML showed favorable tolerability at doses ≤300 mg/d, and consistent, potent FLT3 inhibition at doses ≥80 mg/d. Patients with FLT3 mutation-positive (FLT3mut+) AML receiving doses ≥80 mg/d had an ORR of 52% (CR/CRp/CRi = 41%, PR = 11%) and longer OS than historic experience in R/R AML with combination cytotoxic chemotherapy or other FLT3 TKIs as monotherapy. Given these results, we initiated a phase 3 trial of once-daily (QD) 120 mg gilteritinib. Methods: This randomized, open-label phase 3 study (NCT02421939) will enroll 369 adults with FLT3mut+ AML in first relapse or refractory to front-line therapy. Patients who have not previously received FLT3 inhibitors, except sorafenib and midostaurin, will be randomized 2:1 to either 120 mg gilteritinib QD or the investigator’s pre-randomization specified salvage chemotherapy choice (LoDAC, Aza, MEC, FLAG-IDA), and stratified by prior chemotherapy response and salvage chemotherapy intensity. Gilteritinib or low-intensity chemotherapy cohorts will receive continuous 28-day treatment cycles until a discontinuation event occurs; the high-intensity chemotherapy cohort will receive ≤2 treatment cycles before response measurement. Primary objective is OS; key secondary objectives are event-free survival and CR rate. Other secondary objectives: leukemia-free survival, remission duration, composite CR rate, subsequent transplantation rate, patient-reported fatigue, and safety. A formal interim analysis is planned when ~50% of planned death events have occurred. Study enrollment began on Oct 23, 2015; as of Jan 20, 2017, 167 subjects have been randomized. Clinical trial information: NCT02421939.
A biomarker-directed phase 2 trial of SY-1425, a selective retinoic acid receptor alpha agonist, in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
Authors: Cook Rachel J. , Stein Eytan , Steensma David P. , Sekeres Mikkael A. , Bixby Dale L. , Rizzieri David , Jurcic Joseph G. , Vigil Carlos Enrique , Redner Robert , Roboz Gail J. , Savona Michael R. , McKeown Michael R. , Stephens Kristin , Roth David A. , Cortes Jorge E. 
Published: September 2018

TPS7071 Background: SY-1425 (tamibarotene) is an orally available, synthetic retinoid approved in Japan for the treatment of relapsed/refractory (R/R) APL. SY-1425 is a more potent and selective retinoic acid receptor alpha (RARα) agonist with improved pharmacologic properties compared to all-trans retinoic acid (ATRA) including increased half-life and lack of metabolism by CYP26A1 resulting in extended relative exposures. SY-1425 binding to RARα relieves pathogenic repression of myeloid differentiation. Super-enhancers associated with RARA and upregulation of RARA expression correlate with increased sensitivity to SY-1425 in vitro and predict for response to SY-1425 with induced differentiation and reduced proliferation in RARA-high PDX AML models, but not in RARA-low models. SY-1425 also induces the RARα target gene DHRS3 in RARA-high AML cell lines. This study is designed to demonstrate pharmacodynamic (PD) and clinical effects of SY-1425 in non-APL AML and MDS patients (pts) positive for the RARA super-enhancer associated biomarker or exploratory RARA pathway biomarker, IRF8. Methods: This study is enrolling pts with R/R AML, R/R higher-risk MDS, newly-diagnosed AML ≥60 yrs unlikely to respond to or tolerate standard therapy, and transfusion dependent lower-risk MDS pts without del 5q who are unlikely to respond to or have failed ESAs. Pts must be biomarker positive based on centralized testing of tumor cells from blood. All pts receive SY-1425 at 6 mg/m2/day PO with continuous twice daily dosing. Primary objectives are to characterize the activity of SY-1425 by ORR in AML and higher-risk MDS pts or transfusion independence in lower-risk MDS pts. Secondary objectives include event-free and relapse-free survival, duration of response, overall survival, hematologic improvement and safety. PD evaluation includes induction of DHRS3 and expression of myeloid differentiation markers. Target enrollment is 80 pts. This trial opened in September 2016. Through a protocol amendment, SY-1425 treatment in combination with azacitidine will also be evaluated. ClinicalTrials.gov identifier: NCT02807558.
A randomized, open-label, phase II study of azacitidine (AZA) in combination with durvalumab in patients (pts) with previously untreated higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) ineligible for hematopoietic stem cell transplantation (HSCT).
Authors: Silverman Lewis R. , Dohner Hartmut , Dombret Herve , Mufti Ghulam J. , Stone Richard M. , Rose Shelonitda , Gerike Torsten , Camus Frederic , Fenaux Pierre 
Published: September 2018

TPS7074 Background: Hypomethylating agents (HMAs) induce hematologic response in ~ 50% of higher-risk MDS pts; however, there are few treatment options for nonresponding pts at increased risk of AML progression and death. While older AML pts ineligible for HSCT have similar overall survival (OS) with AZA and chemotherapy (13.3 vs 12.2 months) (Döhner et al. Haematologica 2015;100:P566), there is an opportunity to further improve responses and OS in these pts. Blockade of the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitors is an emerging paradigm in anticancer therapy. PD-L1 is expressed on cells from AML and MDS pts; expression is upregulated on myeloblasts following HMA therapy (Yang et al. Leukemia 2014;28:1280) and during MDS transformation to AML (Ogata et al. Leuk Res 2012;36:1229). Durvalumab (MEDI-4736), a human anti-PD-L1 monoclonal antibody, is well tolerated and induces durable responses in pts with solid tumors (Lutzky et al. JCO 2014;32:3001). This randomized, open-label, phase 2 study evaluates efficacy and safety of subcutaneous (SC) AZA ± durvalumab in pts with higher-risk MDS and older pts with AML. Methods: Eligible MDS pts ( < 20% blasts) aged ≥ 18 years, with IPSS intermediate- or high-risk MDS, and AML pts (≥ 20% blasts) aged ≥ 65 years, are randomized 1:1 to receive either AZA 75 mg/m2 SC for 7/28 days or AZA 75 mg/m2 SC for 7/28 days plus durvalumab 1500 mg IV on day 1 of 28-day cycles. Pts are stratified by cytogenetic risk: intermediate- vs poor-risk AML, and intermediate- vs poor-/very-poor-risk MDS. Primary endpoint is overall response rate per IWG 2006 criteria in MDS pts, and proportion of pts achieving complete response (CR) or CR with incomplete blood count recovery (CRi) per modified IWG 2003 criteria in AML pts. Other endpoints include safety, time to response, overall survival and PD-1/PD-L1 activity. Pts will be followed every 3 months until discontinuation. Target enrollment is 182 pts: 72 MDS pts and 110 AML pts. Enrollment began in June 2016 (ClinicalTrials.gov NCT02775903).
Phase 2 study of the safety and efficacy of INCB050465 in patients with relapsed or refractory (R/R) diffuse large b-cell lymphoma (DLBCL) (CITADEL-202).
Authors: Coleman Morton , Forero-Torres Andres , Ribrag Vincent , Chau Ian , DeMarini Douglas James , Zinzani Pier Luigi 
Published: September 2018

TPS7579 Background: Aberrant activation of PI3Kδ is implicated in B-cell malignancies. INCB050465, a highly selective PI3Kδ inhibitor, is demonstrating preliminary efficacy in an ongoing phase 1/2 dose-escalation and expansion study as monotherapy for r/r DLBCL as well as for other r/r B-cell malignancies (ASH 2016; Abstract 4195). This phase 2 study will further evaluate the efficacy and safety of single-agent INCB050465 in pts with r/r DLBCL. Methods: In this phase 2, multicenter, open-label study (NCT02998476), eligible adults will have r/r DLBCL diagnosis, defined as receiving 1–5 prior treatments and be ineligible for high-dose chemotherapy or autologous stem-cell transplant (SCT). Pts will also have ≥1 measurable lesion (nodal ≥2 cm or extranodal > 1 cm in longest dimension); Eastern Cooperative Oncology Group performance status ≤2; adequate hematologic, hepatic, and renal function; no mediastinal large B-cell lymphoma or CNS metastases; no allogeneic SCT ≤6 months, or graft-versus-host-disease after allogeneic SCT, or autologous SCT ≤3 months, before first dose; and no prior treatment with PI3K inhibitors. Pts will be enrolled into 2 groups according to prior treatment with a Bruton’s tyrosine kinase (BTK) inhibitor (Group A [n = 100, no BTK inhibitor] or B [n≤20, received BTK inhibitor]). Both groups will receive INCB050465 20 mg orally QD for 8 wks; then 20 mg QW until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint is the objective response rate in Group A (complete/partial response per independent review committee based on Lugano criteria). Secondary endpoints will include duration of response, progression-free survival, overall survival, and safety in Group A (these endpoints will be exploratory in Group B). Other exploratory assessments will include pharmacokinetics and association between genetic characteristics and treatment response in both groups. In a planned interim futility analysis of Group A, the study will be terminated if ≤13 of the first 40 treated pts respond (no futility analysis of Group B will be conducted). The study is currently recruiting (estimated completion date, March 2020). Clinical trial information: NCT02998476.
A phase II, open-label, multi-arm study of novel combinations of immunotherapies or DDR inhibitors in platinum-refractory, extensive disease small-cell lung cancer (ED-SCLC): BALTIC.
Authors: Von Pawel Joachim , Vynnychenko Ihor , Jiang Haiyi , Huang Yifan , Dennis Phillip A. 
Published: September 2018

TPS8585 Background: The prognosis of platinum-refractory ED-SCLC is poor, with ~95% of pts failing to respond to topotecan, the only approved 2ndline treatment. SCLC is associated with a high mutation load and genomic instability, and data suggest that enhanced DNA repair could be a resistance mechanism. As such, immunotherapies and DNA damage repair inhibitors may be beneficial in this disease setting. Durvalumab (D) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb against CTLA-4. In a Phase 1b study in NSCLC (NCT02000947), D + T showed encouraging activity and manageable tolerability. AZD1775 is a small-molecule inhibitor of the DNA damage checkpoint kinase WEE1 that potentiates genotoxic chemotherapies and is being developed for the treatment of advanced solid tumors with genetic deficiencies in DNA repair mechanisms. In a Phase 2 study in platinum-refractory p53 mutated ovarian cancer (NCT01164995), AZD1775 + carboplatin showed promising activity and an acceptable safety profile. Methods: BALTIC (NCT02937818) is a Phase 2, open-label, multicenter, multi-arm, exploratory, signal-searching study to assess the preliminary activity of novel treatment combinations in refractory ED-SCLC. Eligible pts will have progressed during, or within 90 days of completing 1st line platinum-based chemotherapy, and have life expectancy ≥8 wks. Each arm is independent and will open sequentially to enroll up to 20 pts. The study will open initially with 2 arms: D 1500 mg + T 75 mg i.v. q4w for 4 doses, followed by D monotherapy 1500 mg i.v. q4w (Arm A); and oral AZD1775 225 mg bid for 2.5 days from Day 1 + carboplatin AUC 5 on Day 1 i.v. q3w (Arm B). Pts will receive treatment until confirmed disease progression or discontinuation. Further arms may be added to assess other combinations once safe and tolerable doses and schedules have been established. The primary endpoint is investigator-assessed ORR (RECIST v1.1). Secondary endpoints include duration of response, disease control rate, time to response, PFS, OS, PK, safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT02937818.
A randomized phase II study of vemurafenib plus cobimetinib continuous versus intermittent in previously untreated BRAF V600-mutation positive patients with unresectable locally advanced or metastatic melanoma.
Authors: Lopez-Martin Jose A. , Berrocal Alfonso , González-Cao María 
Published: September 2018

TPS9599 Background: Previous clinical trials have shown that vemurafenib significantly increases PFS and OS in untreated BRAFV600 mutant advanced melanoma patients. Nevertheless, disease progression occurs after a median of 6-7 months since start of vemurafenib. Several mechanisms of acquired resistance to vemurafenib result in reactivation of MAPK pathway. Upfront addition of a MEK inhibitor (MEKi) to vemurafenib delays secondary resistance to BRAFi. The combination of cobimetinib, a MEKi, plus vemurafenib as a continuous administration was approved by FDA in 2,015 in untreated metastatic BRAFV600 advanced melanoma patients based on an increase in PFS and OS achieved in a phase III trial (coBRIM trial). Preclinical models have shown that continuous vemurafenib dosing promotes the clonal expansion of drug-resistant cells, and intermittent dosing could serve to eliminate the fitness advantage of the resistant cells and delay the onset of drug-resistant disease (Das Thakur, Nature 2013). These observations and some clinical case reports support upfront evaluation of alternative dosing regimens of MAPK pathway inhibition. Methods: This is a randomized phase II study to explore the efficacy and safety of two schedules of administration of vemurafenib in combination with cobimetinib (continuous – 28-day cycles with vemurafenib 960 mg PO BID, Days 1-28, and cobimetinib 60 mg PO QD, Days 1-21 – and intermittent – same dose/schedule during first 12 weeks, and then, same doses with the following schedule: vemurafenib 4 weeks on /2 weeks off, and cobimetinib 3 weeks on/ 3 weeks off), in patients with untreated, BRAFV600 mutated, unresectable, measurable (RECIST 1.1), locally advanced or metastatic melanoma. Prior adjuvant immunotherapy is allowed. Primary endpoint is PFS. Secondary endpoints include: OS, ORR, pharmacokinetic and pharmacodynamic profiles and safety. Additional translational research to analyze predictive factors and mechanism of resistance will be explored. The trial is in progress; 56 of up to 116 planned pts have been recruited at the end of December 2016 (enrollment started in June 2015). Clinical trial information: NCT02583516.
Rethinking the evolution of the human foot: insights from experimental research
Authors: Holowka Nicholas B. , Lieberman Daniel E. 
Published: September 2018

ABSTRACTAdaptive explanations for modern human foot anatomy have long fascinated evolutionary biologists because of the dramatic differences between our feet and those of our closest living relatives, the great apes. Morphological features, including hallucal opposability, toe length and the longitudinal arch, have traditionally been used to dichotomize human and great ape feet as being adapted for bipedal walking and arboreal locomotion, respectively. However, recent biomechanical models of human foot function and experimental investigations of great ape locomotion have undermined this simple dichotomy. Here, we review this research, focusing on the biomechanics of foot strike, push-off and elastic energy storage in the foot, and show that humans and great apes share some underappreciated, surprising similarities in foot function, such as use of plantigrady and ability to stiffen the midfoot. We also show that several unique features of the human foot, including a spring-like longitudinal arch and short toes, are likely adaptations to long distance running. We use this framework to interpret the fossil record and argue that the human foot passed through three evolutionary stages: first, a great ape-like foot adapted for arboreal locomotion but with some adaptations for bipedal walking; second, a foot adapted for effective bipedal walking but retaining some arboreal grasping adaptations; and third, a human-like foot adapted for enhanced economy during long-distance walking and running that had lost its prehensility. Based on this scenario, we suggest that selection for bipedal running played a major role in the loss of arboreal adaptations.
Case Report: Clinical manifestation and dental management of Papillon-Lefèvre syndrome
Authors: Yousry Yasmin Mohamed , EL-Latif Amr Ezzat Abd , El-Gawad Randa Youssef Abd 
Published: September 2018

Background:Papillon-Lefèvre syndrome (PLS) is considered a rare syndrome, which is characterized by the presence of palmar-plantar hyperkeratosis and aggressively progressing periodontitis that finally leads to premature loss of both deciduous and permanent teeth.Case report:A four-year-old Egyptian boy presented with a maternal complaint that her child suffers from early loss of many teeth, presence of loose teeth along with an asymptomatic swelling related to the upper anterior area. The patient was diagnosed with PLS. A symptomatic management and prevention program was followed and the swelling was excised; afterwards diagnosed as peripheral ossifying fibroma.Conclusion:Early recognition and intervention for patients with PLS is essential to avoid the threat of being edentulous if left unmanaged.
Ultrasound imaging aids the learning of the landmark technique for lumbar puncture in novice learners in a secure training environment
Authors: Lundsgaard Rune Sarauw 
Published: September 2018

Background: Performing a lumbar puncture (LP) is a key skill to master for doctors in the emergency department (ED), but the level of success and rate of complications still differs considerably. Studies have shown that LP is attempted at a different level than intended in 30% of cases when the classical landmark technique is used. Ultrasound-assisted LP can reduce the risk of failed LP, possible by its ability to visualize the relevant anatomy of the spine, but only a few studies have considered its potential in learning environments with novice learners. Methods: Medical students and first-year trainee doctors who had never performed a LP in a clinical setting were asked to locate and mark the exact location of where to insert the needle when performing a LP by first using the classical landmark technique secondly by use of ultrasound. Corrections of the marked locations were registered for each attempt. Each participant marked three different healthy volunteers in both sitting and laying positions. Results: The accuracy in LP by landmarking as a total of correct markings (“unchanged”) vs. a total of incorrect markings (“changed”) improved significantly in both the sitting (p = 0.028) and lying positions (p=0.002). All participants were positive about the use of ultrasound when learning how to identify the correct LP marking, mostly because of improved understanding of the anatomical structures and improved confidence in the succeeding attempts. Conclusion: Ultrasound can assist and potentially increase the learning of landmark techniques in novice learners in a secure training environment. Visualizing the underlying anatomical structures of the landmark technique in this way can add a second level of security for the learner for the future practice of LP.