bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of mechano-microenvironment of acral melanoma and its potential impact on tumor cell invasion.
Authors: Yi Xin , Liu Jia yong , Dai Jie , Guo Jun , Wu Cong ying , Si Lu , Mao Lili , Qi Zhong Hui 
Published: May 2019

e21062 Background: Acral melanoma is the main subtype in Asia, and tends to be insensitive to conventional and novel therapies compared with cutaneous melanomas. It has been proved that biomechanical alterations inside the tumor microenvironment significantly affect tumor progression in breast, pancreatic and other cancers(Hepatology. 2016 July ; 64(1): 261–275; Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXXI) . Hence, we hypothesized that the biomechanical microenvironment plays critical roles in proliferation and invasion in acral melanoma. In this study, the main purpose is to observe whether melanoma cells have the same ability called “durotaxis” as other tumors, which to respond to a gradient of extracellular stiffness and migrate in a directed fashion. Methods: In this study, the stiffness was compared between the acral melanoma tissue and the normal tissue by using the atomic force microscope (AFM) with fresh samples and the freezing microtome sectioning specimen (J. Matthew Barnes et al., Nature Cell Biology 2018.) . A stiffness gradient polyacrylamide hydrogel system was constructed to observe how the acral melanoma cells response. Using automated tracking (Curr Protoc Cell Biol. ; 76: 12.12.1–12.12.16.) of positional data for large sample size of single migrating cells to systematically analyze polarized melanoma cell migration in response to stiffness gradient. Results: The results showed that 1) all the acral melanoma cell lines tested displayed strong anti-durotactic migratory response, which was in accordance with the AFM measurement that the melanoma microenvironment gradually softened; 2) Acral melanoma cells tend to move toward softer areas on gradient gels, which is contrary to the migration behavior of most other tumor cells. Conclusions: In this study, we presented the different migratory pattern of acral melanoma cells. It may illustrate the invasion mechanism for aral melanoma cells. It could also herald that extracellular matrix may be a potential therapeutic target in acral melanomas.
Genetic relationship between pilar cysts, pilar tumors and pilar carcinomas.
Authors: Hagen Rachael , Kolodney Joanna Amy , Patterson Jessica , Kolodney Michael 
Published: May 2019

e21063 Background: Pilar cysts, also known as trichilemmal cysts, are common cutaneous nodules that occur sporadically or an autosomal dominant inheritance pattern. A pilar cyst can transform into a proliferating pilar tumor (PPT) or pilar carcinoma. This study aimed to determine the genetic relationships between the malignant variants and the precursor pilar cysts. Methods: We performed whole exome (WES) and Sanger sequencing of pilar cysts and matched blood (or other non-lesional tissue representing systemic DNA) from 17 subjects with multiple familial pilar cysts and 15 with a single, apparently sporadic, pilar cyst. We then performed WES on four subjects with PPTs, one with matched blood, and one subject with a pilar carcinoma matched with blood. Results: We identified a c.2234G > A somatic mutation in phospholipase C delta 1 ( PLCD1), a tumor suppressor gene, in all 21 familial pilar cysts sequenced. In addition, 16 of the 17 subjects with familial pilar cysts were hemizygous for a c.1379G > A germline variant in PLCD1. By contrast, neither of these two mutations were found in subjects with PPTs or the subject with a pilar carcinoma. A potential loss-of-function somatic mutation of the tumor suppressor gene p53 was identified in the subject with a pilar carcinoma. Conclusions: Our results indicate that hereditary pilar cysts are an autosomal dominant tumor syndrome resulting from two hits to the PLCD1 tumor suppressor gene. However, these somatic PLCD1 mutations were not present in the four PPTs or the pilar carcinoma. This suggests that the more aggressive cyst variants originate from sporadic pilar cysts. In addition, our results are consistent with loss of p53 being a key event that causes pilar cysts to evolve into carcinomas as previously proposed.
A phase III, multicenter, randomized, open label trial of [fam-] trastuzumab deruxtecan (DS-8201a) versus investigator’s choice in HER2-low breast cancer.
Authors: Modi Shanu , Ohtani Shoichiro , Lee Caleb C. , Wang Kongming , Saxena Kapil , Cameron David A. 
Published: May 2019

TPS1102 Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have greatly improved survival in HER2+ breast cancer (BC). However, there are many more BC patients with HER2-low expression (immunohistochemistry [IHC] 1+ or 2+/ in situ hybridization-negative), for whom no HER2-targeted therapies are approved. [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a humanized HER2 antibody, peptide-based cleavable linker, and a topoisomerase I inhibitor payload. It has a drug-to-antibody ratio of ~8 and the membrane permeability of the cleaved payload enables a cytotoxic bystander effect. In an ongoing phase 1 trial, T-DXd demonstrated an objective response rate (ORR) of 44.2% (19/43) with a manageable safety profile in heavily pretreated, advanced HER2-low BC (Oct 2018 data cutoff; Modi et al, SABCS 2018). Methods: DESTINY-Breast04 is a randomized, phase 3, 2-arm, open-label, multicenter study comparing efficacy and safety of T-DXd vs physician’s choice in HER2-low, unresectable and/or metastatic BC. Approximately 540 subjects will be randomized 2:1 to T-DXd (5.4 mg/kg intravenous every 3 weeks) or physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Randomization is stratified by HER2 IHC status, number of prior treatments, and prior CDK4/6 inhibitor therapy/hormone receptor (HR) status. HER2 IHC will be assessed and confirmed by central testing based on archival samples. The primary efficacy endpoint is progression-free survival (PFS) per mRECIST v1.1 determined by blinded independent central review. Secondary efficacy endpoints are investigator-assessed PFS, overall survival, confirmed ORR, and duration of response. Safety endpoints include serious adverse events (AEs), treatment-emergent AEs, and AEs of special interest (interstitial lung disease/pneumonitis, cardiotoxicity, and infusion-related reactions). Primary PFS analysis will occur when 318 events are observed in HR+ subjects; providing 90% power to detect a hazard ratio of 0.68 with 1-sided α of 0.025. Enrollment began in Dec 2018. Clinical trial information: NCT03734029.
XENERA-1: A phase II trial of xentuzumab (Xe) in combination with everolimus (Ev) and exemestane (Ex) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) and non-visceral involvement.
Authors: Schmid Peter , Rugo Hope S. , Cortes Javier , Huang Chin-Lun , Crossley Kate , Massey Dan , Burris Howard A. 
Published: May 2019

TPS1103 Background: The mTOR inhibitor Ev, combined with Ex, is a mainstay in the treatment of post-menopausal women with advanced HR+/HER2- BC. However, the activity of Ev is limited by counter-regulatory feedback mechanisms in cancer cells, involving reactivation of insulin-like growth factor (IGF)/mTOR survival signaling. Combining Ev with the humanized IGF-1 and IGF-2 ligand-blocking antibody Xe abrogates this feedback, thus intensifying inhibition of tumor growth; this leads to a pronounced effect in patients with non-visceral (e.g., bone and lymph node) metastases. The phase II XENERA-1 trial evaluates the combination of Xe with Ev and Ex in post-menopausal women with HR+/HER2- BC. Methods: XENERA-1 (NCT03659136) is a double-blind, placebo-controlled, randomized study to assess the efficacy and safety of Xe in combination with Ev and Ex, in post-menopausal women with HR+/HER2- locally advanced/mBC and non-visceral disease. The population comprises post-menopausal mBC patients who have progressed on ≤1 previous line of a non-steroidal aromatase inhibitor, with or without a CDK 4/6 inhibitor, who may have received fulvestrant. Other inclusion criteria are: an Eastern Cooperative Oncology Group Performance Status of 0 or 1; adequate organ function; and non-visceral disease (absence of brain, liver, lung, peritoneal or pleural metastases). Patients are randomized (1:1) to receive Xe (1000 mg/week, iv) or placebo (weekly, iv), in combination with Ev (10 mg/day) and Ex (25 mg/day). Treatment will continue until disease progression, unacceptable toxicity or other reasons. The primary endpoint is progression-free survival according to RECIST 1.1 criteria, by independent review. Secondary endpoints are: overall survival; disease control; duration of disease control; objective response; and time to progression of pain/intensification of palliation. Safety and pharmacokinetic endpoints, and exploratory biomarkers will also be evaluated. The first patient was enrolled in January 2019; target enrollment is 80 patients in 12 countries. Clinical trial information: NCT03659136.
CONTESSA: A multinational, multicenter, randomized, phase III registration study of tesetaxel plus a reduced dose of capecitabine in patients (pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (LA/MBC) who have previously received a taxane.
Authors: O'Shaughnessy Joyce , Piccart Martine , Schwartzberg Lee S. , Cortes Javier , Harbeck Nadia , Im Seock-Ah , Rugo Hope S. , Untch Michael , Yardley Denise A. , Bondarenko Igor , Chan Stephen , Dieras Veronique , Pegram Mark D. , Kroll Stew , O'Connell Joseph P. , Vacirca Jeff , Wei Thomas , Tang Kevin , Seidman Andrew David 
Published: May 2019

TPS1107 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing regimen; no observed hypersensitivity reactions; preclinical evidence of CNS penetration; and improved activity against chemotherapy-resistant tumors. Over 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a Phase 2 study in 38 pts with HER2-, HR+ MBC who received T Q3W, with a confirmed ORR per RECIST 1.1 of 45% and median PFS of 5.4 mo. The confirmed ORR in taxane-pretreated pts was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine (C) in combination with a taxane may result in reduced toxicity without reduction in efficacy. Preclinical data also suggest that T may penetrate the brain at clinically relevant concentrations. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ LA/MBC, with revised eligibility criteria to allow inclusion of pts with CNS metastases. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ LA/MBC previously treated with a taxane in the (neo)adjuvant setting. The protocol was newly amended to allow pts with known CNS metastases. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR, and disease control rate. Enrollment began in Dec 2017. Following review in Jan 2019, the Independent Data Monitoring Committee recommended that the Study continue as planned. Clinical trial information: NCT03326674.
SGNLVA-002: Single-arm, open label phase Ib/II study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer.
Authors: Han Hyo S. , Alemany Carlos A. , Brown-Glaberman Ursa Abigail , Pluard Timothy J. , Sinha Rajni , Sterrenberg Danielle , Albain Kathy S. , Basho Reva K. , Biggs David , Boni Valentina , Diab Sami , Tsai Michaela L. , Tkaczuk Katherine Hanna , Wang Yinghui , Wang Zejing , Meisel Jane Lowe 
Published: May 2019

TPS1110 Background: There are currently no curative treatments for patients with metastatic triple-negative breast cancer (mTNBC), and prognosis for this disease is very poor. Emerging treatment combinations of anti-programmed death ligand 1 (PD-L1) agents with chemotherapy have shown promise in mTNBC. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1, which is highly expressed in breast cancer cells. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death (ICD). Preliminary results from an ongoing phase 1 study of LV monotherapy has shown LV to be well tolerated and to have encouraging antitumor activity in patients with mTNBC. Combining LV and pembrolizumab may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-L1 activity. Methods: This single-arm, open-label, phase 1b/2 study evaluates the safety and antitumor activity of LV in combination with pembrolizumab as first-line therapy for patients with unresectable locally advanced or mTNBC (NCT03310957, 2017-002289-35). Patients must have measureable disease per RECIST v1.1, an ECOG score of 0 or 1, and no prior cytotoxic or anti-PD-L1 treatment for advanced disease. This study has 2 parts that are enrolling sequentially: a dose-finding phase that starts at LV 2.5 mg/kg + pembrolizumab 200 mg intravenously every three weeks, and a dose expansion phase. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab, and identify the recommended phase 2 dose of LV. The secondary objectives are to assess duration of response, disease control rate, progression-free survival, and overall survival. Additional objectives include assessing PD-L1 and LIV-1 expression-response relationship. Study enrollment is ongoing in the US and EU. Clinical trial information: NCT03310957.
Nimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer.
Authors: Barroso-Sousa Romualdo , Trippa Lorenzo , Lange Paulina , Andrews Chelsea , McArthur Heather L. , Haley Barbara B. , Rugo Hope S. , Emens Leisha A. , Winer Eric P. , Mittendorf Elizabeth A. , Tolaney Sara M. 
Published: May 2019

TPS1115 Background: A previous study from our group showed that approximately 9% of metastatic breast cancer (MBC) is hypermutated, defined as a tumor mutational burden (TMB) ≥10 Mutations/Megabase (Mut/Mb). The aim of this study is to evaluate if patients with hypermutated HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/Kg intravenously (IV) every 14 days plus Ipilimumab 1 mg/Kg IV every 6 weeks in subjects with hypermutated metastatic HER2-negative breast cancer. Patients with measurable HER2-negative MBC, TMB ≥10 Mut/Mb assessed by a cancer-gene panel evaluating > 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting are eligible. The primary objective is overall response rate according to RECIST 1.1. Secondary objectives include the safety and tolerability of the combination, progression-free survival, and overall survival. The study will follow a two-stage design. In the first stage 14 patients will be enrolled. If there is at least one patient with objective response, accrual will continue to the second stage where an additional 16 patients will be enrolled. If there are at least 4 patients with an objective response among the 30 patients, the regimen will be considered worthy of further study. If the true response rate is 5%, the chance the regimen is declared worthy of further study is less than 5%. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is > 90%. Tumor biopsies, peripheral blood, and stool collection are mandatory and will be obtained at baseline, on treatment (end of cycle 1), and at disease progression and will be assessed for potential biomarkers of treatment response. The trial was activated in February 2019, and accrual should be completed in 18 months. Clinical trial information: NCT03789110.
A phase II study of PD-1 inhibition for the prevention of colon adenomas in patients with Lynch syndrome and a history of partial colectomy.
Authors: Jeter Joanne M. , Hampel Heather , Stanich Peter , Pearlman Rachel , Hinton Alice , Hays John L. , Goldberg Richard M. 
Published: May 2019

TPS1587 Background: Colon cancers and adenomas that are associated with Lynch syndrome (LS) often display microsatellite instability (MSI), a characteristic that is associated with increased response to treatment with PD-1 inhibitors. Because LS patients with a history of colon cancer are at increased risk of having a second primary colon cancer or high-risk adenoma, preventive measures are of particular interest in this population. We hypothesize that a maintenance schedule of nivolumab can be safely administered to LS patients with a history of treated colon cancer with remaining colon at risk in order to decrease the incidence of adenomas, advanced adenomas and second primary colon cancers. Methods: OSU 17198 is a phase II multi-center, single-arm study of nivolumab in patients with germline MLH1 or MSH2 mutations and a history of hemicolectomy for colon cancer at least one year prior to study entry. Subjects must have completed any adjuvant therapy at least 6 months prior to study participation and may not have received prior therapy with a PD-1 inhibitor. Nivolumab is given at 240mg IV every 3 months for two years, and colonoscopies will be performed prior to study entry, after the fourth dose, after the eighth dose, and one year after the eighth dose. Subjects will be monitored for auto-immune adverse effects. The primary endpoint is incidence of adenomas at three years, and secondary endpoints are safety, incidence of advanced adenomas, and incidence of colon and non-colon cancers at three years. Approximately 104 subjects will be enrolled to obtain 94 evaluable subjects. This study is currently open for enrollment at the Ohio State University and at various stages of activation at seven additional sites in the United States. Enrollment of this study is anticipated to be completed in 2020, and data collection is anticipated to be complete in 2023. This study has undergone safety review by the FDA and the Ohio State University Institutional Review Board. Clinical trial information: NCT03631641.
Oral DNA vaccination targeting VEGFR-2 combined with anti-PD-L1 avelumab in patients with progressive glioblastoma, a phase I/II study: NCT03750071.
Authors: Wick Wolfgang , Wick Antje , Platten Michael , Chinot Olivier L. , Van Den Bent Martin J. , Dhermain Frederic , Mansour Marc , Podola Lilli , Lubenau Heinz 
Published: May 2019

TPS2076 Background: The vaccine (VXM01) is a VEGFR-2 coding DNA vaccine, using a Salmonella Ty21a carrier for oral application. VEGFR-2 is over-expressed in glioblastoma and serves as a promising target for VEGFR-2 primed T cells with the potential to alter tumor angiogenesis and/or eliminate VEGFR-2 expressing tumor cells. VXM01 was well tolerated in a previous phase I/II study involving 14 patients with progressive glioblastoma multiforme. Immunological correlates of vaccination and anti-tumor immunity in the blood and in the tumor were detected. At least one objective clinical response was attributed to vaccine monotherapy, with one more PR achieved in combination with nivolumab. Prolonged overall survival was associated with peripheral immune responses against VEGFR-2, J Clin Oncol 36, 2018 (suppl; abstr 2017). A combination study with the anti PD-L1 checkpoint inhibitor monoclonal antibody avelumab is currently underway. Methods: A multicentre, open-label phase I/II study ( EudraCT.gov no. 2017-003076-31), will enrol 30 patients with progressive glioblastoma, previously treated with temozolomide/radiotherapy. The primary objective is to evaluate safety and tolerability of the vaccine in combination with avelumab. In a 1+2 safety run in, two cohorts of non-reoperable patients will be vaccinated with one of 2 doses of the oral vaccine (106 or 107 CFU) with concurrent intravenous avelumab. After safety evaluation and recommendation of study continuation by the Data Safety Monitoring Board, 18 non-re-operable and 6 re-operable patients will be treated with 107 CFU of the vaccine + avelumab. Vaccinations for all patients will be on day 1, 3, 5, and 7, followed by 4-weekly boosts until progression. Avelumab 800 mg will be administered every two weeks until progression. The enrolment of cohort 1 started with inclusion of the 1st patient in November 2018. The end of study is week 60. Follow up visits will be on months 1, 3, 6, 12 and 24. Objective response rate (ORR), clinical response using iRano criteria, immunological correlates before and after treatment using ELISpot, FACS, TCR-sequencing, IF, and IHC laboratory methods. Clinical trial information: NCT03750071.
A first-in-human study of KY1044, a fully human anti-ICOS IgG1 antibody as monotherapy and in combination with atezolizumab in patients with selected advanced malignancies.
Authors: Quaratino Sonia , Sainson Richard , Thotakura Anil , Henderson Simon J , Pryke Kerstin , Newton Anthea , Brennan Nuala , Oelmann Elisabeth 
Published: May 2019

TPS2644 Background: The Inducible T-cell costimulator (ICOS/CD278) is related to the CD28 superfamily and is induced upon T cell activation. There is a hierarchical order of ICOS expression level, in which highly immunosuppressive TReg (CD4+Foxp3+) present in the tumor microenvironment (TME) are at the top level of expression and CD8 TEff cells are at the bottom level. In addition, ICOS expression on TRegs is higher in the TME than in the blood or spleen. Methods: KY1044, a fully human anti-ICOS IgG1 kappa monoclonal antibody, selectively binds to ICOS with high affinity (which is maintained at intratumoral acidic pH) and has a dual mechanism of action: it promotes the preferential depletion of intratumoral ICOSHigh TRegs resulting in an increase in the TEff:TReg ratio in the TME; and it stimulates ICOSLow TEff cells. Preclinical data demonstrate that KY1044 monotherapy or in combination with anti-PD-L1 is associated with immune cell activation and anti-tumor response. In order to validate the dual mechanism of action in vivo, studies in mice and cynomolgus monkeys were conducted. Firstly, KY1044 injected i.v. at doses up to 100 mg/kg weekly were well tolerated in non-human primates. In addition, pharmacodynamic studies in mice and cynomolgus monkey confirm preferential depletion of ICOSHigh cells. KY1044-CT01 is an open-labelled first in human Phase I/II study assessing the safety, tolerability, PK, PD and anti-tumor activity of KY1044 administered every 3 weeks (Q3W) as an i.v. single agent infusion and in combination with atezolizumab (1200 mg, Q3W IV) in adult patients with advanced/metastatic malignancies. The primary endpoint of the Phase I dose escalations, designed as sequential but overlapping arms of KY1044 monotherapy and combination with atezolizumab, is safety and tolerability. Secondary endpoints are the characterization of pharmacokinetic, pharmacodynamic and efficacy profiles in all patients. In the Phase II part, the primary endpoint is overall response rate (ORR), and the measure of clinical efficacy will be confirmed as per RECIST 1.1. and immune-related (ir)RECIST. An intensive biomarker plan is integral to the study design to underpin the phenotypic and molecular changes in both peripheral blood and tumor. Clinical trial information: NCT03829501.