bluuebunny/crossref_metadata_2025_split huggingface dataset:
eMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.
Authors: Tolaney Sara M. , Fallowfield Lesley , Kaufman Peter A. , Ciruelos Eva M. , Gainford Mary Corona , Lu Yi , Hurt Karla , Wasserstrom Heather Ann , Chen Yanyun , Goel Shom 
Published: June 2021

TPS596 Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.
TrilynX: A phase 3 trial of xevinapant and concurrent chemoradiation for locally advanced head and neck cancer.
Authors: Bourhis Jean , Burtness Barbara , Licitra Lisa F. , Nutting Christopher , Schoenfeld Jonathan D. , Ait Sarkouh Rafik , Bouisset Florilene , Nauwelaerts Heidi , Urfer Yulia , Zanna Claudio , Cohen Ezra E.W. 
Published: June 2021

TPS6091 Background: Concurrent chemoradiotherapy (CRT) is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinomas of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements of xevinapant versus placebo in addition to standard chemoradiation (CRT) for locoregional control (LRC) rate at 18 months, PFS and OS. The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. Methods: TrilynX is a multinational, Phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-HNSCC. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharynx, larynx and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ̃90% power to detect the expected hazard ratio benefit of 0.73. Secondary end-points include OS, PFS, LRC, ORR, HRQL, and safety. Data driven design, patients will be followed up for a minimum of 60-months. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and it is ongoing. References: [1] X. Sun et. al, Lancet Oncol; 21(9): 1173-1187, 2020. [2] J. Bourhis et al., Ann Oncol; 31 (suppl 4): LBA39, 2020. Clinical trial information: NCT04459715.
Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL).
Authors: Jurczak Wojciech , Zinzani Pier Luigi , Cunningham David , Yavrom Sharon , Huang Wenying , Gorbatchevsky Igor , Ribrag Vincent 
Published: June 2021

TPS7573 Background: Patients (pts) with iNHL treated with front-line immunochemotherapy may benefit from an alternative, chemotherapy-free regimen at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3Kδ inhibitor, achieved an 87% response rate, with median duration of response not reached in iNHL when given as a monotherapy or in combination with R. A low rate ( < 10%) of Grade ≥ 3 immune-mediated adverse events of special interest associated with PI3kδ inhibitors is observed in patients administered zandelisib on an intermittent schedule (IS) (JCO 2020 38:15_suppl, 8016). An open-label, phase 2 study (TIDAL, NCT03768505) of zandelisib as monotherapy is ongoing in pts with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: The COASTAL study is a randomized, open-label, controlled multicenter phase 3 trial to investigate the safety and efficacy of zandelisib in combination with R versus standard immunochemotherapy in pts with iNHL. Key eligibility criteria: adults with relapsed or refractory FL or MZL who received ≥1 prior lines of therapy which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide (L); at least one bi-dimensionally measured lesion > 1.5 cm; adequate bone marrow, renal and hepatic function; ECOG performance status score of 0 to 1. Key exclusion criteria: histologically confirmed diagnosis of FL grade 3b or transformed disease; administration of 2 prior immunochemotherapy regimens; prior PI3K inhibitor therapy; known lymphomatous involvement of the central nervous system. Subjects will be randomized 1:1 to receive R-zandelisib or immunochemotherapy (R-CHOP or R-B) and stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy. Zandelisib will be given in a 28-day cycle comprising of daily dosing for 2 cycles followed by IS dosing on days 1-7 of each 28-day subsequent cycle for a duration of 2 years. Rituximab or immunochemotherapy will be given for a total of 6 cycles. Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter. The primary efficacy endpoint is progression-free survival. The major secondary endpoints include ORR, complete response rate, overall survival, and safety. The trial will enroll approximately 534 pts in ̃200 sites globally and will begin enrollment in mid-2021. Clinical trial information: NCT04745832.
Randomized, double-blind, placebo-controlled phase 3 study of ibrutinib plus rituximab in patients with previously untreated marginal zone lymphoma (MZL).
Authors: Noy Ariela , Hughes Stephanie , Biggar Erin , Bogdan Matthew 
Published: June 2021

TPS7576 Background: First-line treatment options for patients with MZL include single-agent immunotherapy, chemotherapy, or chemoimmunotherapy. While chemoimmunotherapy has a higher toxicity profile than immunotherapy alone, it may lead to longer progression-free survival (PFS). Rituximab, an anti-CD20 antibody, is FDA approved for the first-line treatment of follicular lymphoma but not specifically for advanced MZL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved in the United States for patients with MZL who require systemic therapy and have received ≥1 prior anti-CD20-based therapy. The combination of ibrutinib and rituximab has proven effective and is well tolerated in other B-cell lymphomas; it may serve as an effective chemotherapy-free option for the treatment of previously untreated MZL. Methods: NCT04212013 is a multicenter, double-blind, placebo-controlled, randomized, phase 3 study designed to compare the efficacy of ibrutinib + rituximab vs placebo + rituximab in patients with previously untreated MZL. Adults (≥18 y) with histologically documented MZL (splenic, nodal, and extranodal subtypes), no prior systemic treatment for MZL (prior splenectomy or other local surgical or radiation treatment allowed), measurable disease on CT scan, documented evidence of need for treatment, and Eastern Cooperative Oncology Group performance status ≤2 are eligible. Patients will be randomly assigned 1:1 to receive ibrutinib 560 mg once daily or placebo; all patients will also receive rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1. Subcutaneous dosing after dose 1 is allowed. Treatment with ibrutinib or placebo will continue for 30 mo or until disease progression, unacceptable toxicity, patient or investigator decision to withdraw, noncompliance, death, or study termination. Clinical assessments will occur every 4 weeks until week 13, at week 25, and then every 6 mo thereafter. Imaging assessments will be conducted at week 13, at week 25, and then every 6 mo thereafter. Response will be investigator assessed per the revised International Working Group for Non-Hodgkin Lymphoma (RECIL) criteria. At month 30, patients who have a complete response (CR) will discontinue treatment; patients who have a partial response (PR) or stable disease may continue treatment at investigator discretion. Safety will be assessed throughout the study and for 30 days after the last dose of study treatment. The primary endpoint is CR rate at month 30. Secondary endpoints include overall response rate (CR + PR), duration of response, PFS, overall survival, and safety. Enrollment has started and will continue until approximately 138 patients are enrolled. Clinical trial information: NCT04212013.
CAcTUS: A parallel arm, biomarker driven, phase II feasibility trial to determine the role of circulating tumor DNA in guiding a switch between targeted therapy and immune therapy in patients with advanced cutaneous melanoma.
Authors: Lee Rebecca , Rothwell Dominic G. , Chow Shien , Shaw Heather May , Turajlic Samra , Smith Nigel , Clipson Alexandra , Clarke Harry , Kelso Noel , Mitchell Jackie , Sutton Chris , Sylvestre Gema , Nathan Paul D. , Larkin James , Corrie Philippa Gail , Plummer Elizabeth Ruth , Marais Richard , Dive Caroline , Lorigan Paul 
Published: June 2021

TPS9587 Background: Circulating tumor DNA (ctDNA; the tumour derived fraction of circulating free DNA in the blood) has been shown to be a biomarker of tumor burden/progression in many cancers. We recently accurately monitored treatment response and resistance in stage IV melanoma by ctDNA analysis in serial peripheral blood samples. Pre-clinical data has previously revealed that BRAF inhibition provokes a micro-environment with increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines that could enhance immune responses. We aimed to test the hypothesis that ctDNA could be implemented as a personalised, real-time liquid biopsy to identify when tumours are responding to targeted therapy in order optimise a switch to immunotherapy. Methods: We validated the ctDNA assays for BRAF mutation calling as a primary trial endpoint. We designed a phase II multicenter, parallel arm study across 6 UK sites, to assess primary objectives of i). Whether a ctDNA result can be turned around within 7 days and actioned in a clinically relevant timeframe ii). to assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% from baseline on targeted therapy is an appropriate ‘cut off’ to instruct switching to immunotherapy. Secondary endpoints include Overall Response Rate (ORR) to immunotherapy, radiological/clinical and ctDNA determined progression free survival (PFS) on each treatment. Forty patients are planned based on inclusion criteria of stage IV or stage III unresectable cutaneous BRAF mutant melanoma, baseline ctDNA BRAF variant allele frequency (VAF) ≥1.5%, ECOG 0/1/2, no symptomatic brain metastases, no prior adjuvant nivolumab plus ipilimumab (N+I). Prior adjuvant dabrafinib + trametinib (D+T) is allowed as long as recurrence is >6 months from completion. Patients are randomised 1:1 to either standard Arm A; investigator choice of either D+T (150mg BD +2mg OD respectively) or N+I (1 mg/kg N +3 mg/kg I q3 wkly, then N 480mg q4 wkly) first line, then switch on progression to the other treatment. In the experimental Arm B; all patients start on D+T and have BRAF ctDNA monitored q2 wkly for 4 wks then q4 wkly. When ≥80% decrease vs. baseline in ctDNA BRAF VAF occurs, patients switch to N+I. If patients subsequently progress on N+I, they will resume D+T. The study is open with 9 patients enrolled at time of submission. Clinical trial information: NCT03808441.
Overcoming Barriers to Clinical Trial Participation: Outcomes of a National Clinical Trial Matching and Navigation Service for Patients With a Blood Cancer
Authors: Sae-Hau Maria , Disare Kate , Michaels Margo , Gentile Alissa , Szumita Leah , Treiman Katherine , Weiss Elisa S. 
Published: June 2021

PURPOSE: There are numerous barriers to cancer clinical trial participation in the United States. This paper describes the approach and outcomes of The Leukemia & Lymphoma Society's Clinical Trial Support Center (CTSC), whose nurse navigators assist patients with a blood cancer and their oncologists by identifying all appropriate trials based on clinical data and patient preference, facilitating informed and shared decision making, and minimizing enrollment barriers. METHODS: Data on patients served from October 2017 to October 2019 were analyzed using bivariate and multivariate analyses to determine demographic and clinical characteristics associated with enrollment. Reasons for nonenrollment were examined. RESULTS: The CTSC opened 906 patient cases during this time frame. Among all US patients with a closed case (n = 750), the clinical trial enrollment rate was 16.1%. Among those with a known enrollment outcome after a trial search (n = 537), the enrollment rate was 22.5%. Multivariate analysis controlling for variables significant in bivariate analyses (insurance, treatment status, Eastern Cooperative Oncology Group performance status, and urban or rural residence) revealed that patients with Medicaid were less likely to enroll than those with private or commercial insurance (adjusted odds ratio, 0.054; CI, 0.003 to 0.899), and patients in treatment or maintenance were less likely to enroll than those relapsed or refractory to most recent therapy (adjusted odds ratio, 0.312; CI, 0.139 to 0.702). Primary reasons for nonenrollment were preference for standard of care (66.3%) and patient passed away (16.1%). CONCLUSION: The CTSC is an effective, replicable model for addressing multilevel barriers to clinical trial participation. The findings highlight the need to increase opportunities for trial participation sooner after diagnosis and among patients with Medicaid.
GCM2 Silencing in Parathyroid Adenoma Is Associated With Promoter Hypermethylation and Gain of Methylation on Histone 3
Authors: Singh Priyanka , Bhadada Sanjay Kumar , Dahiya Divya , Saikia Uma Nahar , Arya Ashutosh Kumar , Sachdeva Naresh , Kaur Jyotdeep , Behera Arunanshu , Brandi Maria Luisa , Rao Sudhaker Dhanwada 
Published: June 2021

Abstract

Context
Glial cells missing 2 (GCM2), a zinc finger-transcription factor, is essentially required for the development of the parathyroid glands.

Objective
We sought to identify whether the epigenetic alterations in GCM2 transcription are involved in the pathogenesis of sporadic parathyroid adenoma. In addition, we examined the association between promoter methylation and histone modifications with disease indices.

Methods
Messenger RNA (mRNA) and protein expression of GCM2 were analyzed by reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in 33 adenomatous and 10 control parathyroid tissues. DNA methylation and histone methylation/acetylation of the GCM2 promoter were measured by bisulfite sequencing and chromatin immunoprecipitation–qPCR. Additionally, we investigated the role of epigenetic modifications on GCM2 and DNA methyltransferase 1 (DNMT1) expression in parathyroid (PTH)-C1 cells by treating with 5-aza-2′-deoxycytidine (DAC) and BRD4770 and assessed for GCM2 mRNA and DNMT1 protein levels.

Results
mRNA and protein expression of GCM2 were lower in sporadic adenomatous than in control parathyroid tissues. This reduction correlated with hypermethylation (P &lt; .001) and higher H3K9me3 levels in the GCM2 promoter (P &lt; .04) in adenomas. In PTH-C1 cells, DAC treatment resulted in increased GCM2 transcription and decreased DNMT1 protein expression, while cells treated with the BRD4770 showed reduced H3K9me3 levels but a nonsignificant change in GCM2 transcription.

Conclusion
These findings suggest the concurrent association of promoter hypermethylation and higher H3K9me3 with the repression of GCM2 expression in parathyroid adenomas. Treatment with DAC restored GCM2 expression in PTH-C1 cells. Our results showed a possible epigenetic landscape in the tumorigenesis of parathyroid adenoma and also that DAC may be a promising avenue of research for parathyroid adenoma therapeutics.
Endocrine Toxicity and Outcomes in Patients With Metastatic Malignancies Treated With Immune Checkpoint Inhibitors
Authors: Al Ashi Suleiman I , Thapa Bicky , Flores Monica , Ahmed Ramsha , Rahim Shab E Gul , Amir Maryam , Alomari Mohammad , Chadalavada Pravallika , Morrison Shannon L , Bena James F , Hercbergs Aleck , Lashin Ossama , Daw Hamed 
Published: June 2021

Abstract

Context
Immune checkpoint inhibitors (ICIs) have gained a revolutionary role in management of many advanced malignancies. However, immune-related endocrine events (irEEs), have been associated with their use. irEEs have nonspecific clinical presentations and variable timelines, making their early diagnosis challenging.

Objective
To identify risk factors, timelines, and prognosis associated with irEEs development.

Design and Setting
Retrospective observational study within the Cleveland Clinic center.

Patients
Metastatic cancer adult patients who received ICIs were included.

Methods
570 charts were reviewed to obtain information on demographics, ICIs used, endocrine toxicities, cancer response to treatment with ICI, and overall survival.

Main Outcome Measures
Incidence of irEEs, time to irEEs development and overall survival of patients who develop irEEs.

Results
The final cohort included 551 patients. The median time for the diagnosis of irEEs was 9 weeks. Melanoma was associated with the highest risk for irEEs (31.3%). Ipilimumab appeared to have the highest percentage of irEEs (29.4%), including the highest risk of pituitary insufficiency (11.7%), the most severe (Grade 4 in 60%) and irreversible (100%) forms of irEEs. Forty-five percent of patients with irEEs had adequate cancer response to ICI compared to 28.3% of patients without irEEs (P = 0.002). Patients with irEEs had significantly better survival compared to patients without irEEs (P &lt; 0.001).

Conclusions
In the adult population with metastatic cancer receiving treatment with ICI, irEEs development may predict tumor response to immunotherapy and a favorable prognosis. Ipilimumab use, combination ICI therapy, and melanoma are associated with a higher incidence of irEEs.
Who Stays at Home? The Politics of Social Distancing in Brazil, Mexico, and the United States during the COVID-19 Pandemic
Authors: Testa Paul F. , Snyder Richard , Rios Eva , Moncada Eduardo , Giraudy Agustina , Bennouna Cyril 
Published: June 2021

Abstract
Context: Reductions in population mobility can mitigate COVID-19 virus transmission and disease-related mortality. But do social distancing policies actually change population behavior and, if so, what factors condition policy effects?
Methods: We leverage subnational variation in the stringency and timing of state-issued social distancing policies to test their effects on mobility across 109 states in Brazil, Mexico, and the United States. We also explore how conventional predictors of compliance, including political trust, socioeconomic resources, health risks, and partisanship, modify these policy effects.
Findings: In Brazil and the United States, stay-at-home orders and workplace closures reduced mobility, especially early in the pandemic. In Mexico, where federal intervention created greater policy uniformity, workplace closures produced the most consistent mobility reductions. Conventional explanations of compliance perform well in the United States but not in Brazil or Mexico, apart from those emphasizing socioeconomic resources.
Conclusions: In addition to new directions for research on the politics of compliance, the article offers insights for policy makers on which measures are likely to elicit compliance. Our finding that workplace closure effectiveness increases with socioeconomic development suggests that cash transfers, stimulus packages, and other policies that mitigate the financial burdens of the pandemic may help reduce population mobility.