bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of bavituximab in combination with nivolumab on tumor immune response in a 3D ex vivo system of lung cancer patients.
Authors: Mediavilla-Varela Melanie , Page Melba Marie , Kreahling Jenny , Freimark Bruce D , Shan Joseph , Kallinteris Nikoletta Lea , Antonia Scott Joseph , Altiok Soner 
Published: September 2018

e23091 Background: Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Our previous studies showed that bavituximab enhances the activation of CD8+ TILs that correlates with increased cytokine production by lymphoid and myeloid cells in lung cancer with low PD-L1 expression suggesting that the interruption of the PD-1/PD-L1 axis by nivolumab may enhance the bavituximab effect in tumors. Methods: Fresh tumor tissues obtained from consented patients with NSCLC at the time of surgical resection were utilized in a 3D ex vivo tumor miscrosphere assay, where 3D tumor microspheres were treated with bavituximab or nivolumab alone or in combination at 10 mg/ml for 36 hours. At the end of the treatment, a multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines, including human IFNg, in culture media as a surrogate of TIL activation. In addition, a gene expression analysis using a NanoString platform containing probes to quantitate 770 immune function genes. Results: Preliminary results indicate the combination treatment with bavituximab and nivolumab led to increased expression of genes involved in M1 polarization of tumor associated macrophages in a subpopulation of lung tumors that closely correlated with release of cytokines such as MIP1b (CCL4) which is a chemoattractant for natural killer cells, monocytes and a variety of other cells involved in tumor immune response. Conclusions: This lung patient derived ex-vivo approach indicates that bavituximab in combination with nivolumab may enhance immune response. This response likely involves M1 polarization of tumor associated macrophages and suggests potential clinical implications in the treatment of lung cancer.
Metabolic intratumor heterogeneity of breast cancer.
Authors: Giskeødegård Guro Fanneløb , Badia Marina Perea , Bofin Anna , Madssen Torfinn Støve , Lundgren Steinar , Fjøsne Hans , Bathen Tone Frost 
Published: September 2018

e23095 Background: Breast tumors are highly heterogeneous due to subpopulations of cancer cells that differ in genetic and phenotypic characteristics. Tumor heterogeneity has been associated with treatment resistance and relapse. Therefore, it can be questioned how representative one biopsy is for the whole tumor. Tumor phenotypic heterogeneity cannot be solely attributed to genetic differences, as epigenetics and interaction with the tumor microenvironment also contribute. In this study we have examined intra-tumor heterogeneity by measuring metabolite expression in breast cancer tissue compared with fibroadenomas. Methods: Fresh frozen tissue slices from surgically removed breast tumors were used. Five cores from different areas of the slices were drilled out from 10 tumors; 6 invasive ductal carcinomas grade 2-3, and 4 fibroadenomas. Histological examination of HES-stained sections from each core was done, and metabolic profiling was performed by magnetic resonance spectroscopy (MRS). The relative concentrations of 23 metabolites were quantified. Metabolic heterogeneity was assessed by coefficient of variation (CoV) and PLSDA classification was used for prediction of tumor origin. Results: Cancer tissue showed significantly higher heterogeneity than fibroadenomas for 16/23 metabolites (mean CoV range: 0.15-0.94 for cancer samples, 0.09-0.37 for fibroadenomas, p < 0.05). However, 23/50 samples did not contain tumor tissue on histological examination. After exclusion of tumor-free samples, the heterogeneity of 3 metabolites (glycine, glycerophosphocholine (GPC) and phosphocholine (PCho) remained significantly different between cancer and fibroadenomas (mean CoV range: 0.12-0.65 for cancer, 0.07-0.42 for fibroadenomas, p < 0.05). GPC and PCho are involved in building of cell membranes and may reflect cell-turnover. Multivariate classification could correctly predict which patient a sample belonged to with 78% accuracy. Conclusions: Metabolic heterogeneity could partly be explained by differences in tumor cell and stromal content, and the origin of an unknown sample could be successfully predicted, showing that metabolic intratumor heterogeneity is smaller than the heterogeneity between patients.
Verification of targeted gene expression profiling panel for identifying biomarker signatures for immunotherapy research.
Authors: Pankov Aleksandr , Ku Yuan-Chieh , Tom Warren , Zheng Jianping , Sun Yongming , Looney Timothy , Looney Timothy , Au-Young Janice , Mongan Ann , Hyland Fiona 
Published: September 2018

e23208 Background: Immunotherapy has led to an unprecedented and long-lasting response in susceptible populations. Despite the therapeutic potential of the treatment, identifying biomarkers and stratifying populations that are likely to respond has been a challenge. While gene expression profiling has previously been successfully used to stratify individuals, there exist limitations with the prevalent technologies. In particular, full transcriptome gene expression estimates use limited biological material to measure the concentrations of thousands of uninformative genes and often lacks the depth required to accurately measure expression of lowly-expressed genes. These low-expressing genes may be critical to the identification of a signature associated with susceptible population. Methods: To efficiently measure the expression of the genes potentially informative of an immunotherapy response, we developed a high-throughput targeted gene expression solution measured with our RNA Ion Oncomine™ Immune Response Research Assay panel* containing 395 genes. This panel provides information about the expression of genes involved in tumor checkpoint inhibition, as well as markers of T cell signaling pathway, interferon signaling, tumor infiltrating lymphocytes (TIL). Results: We used publicly-available TCGA data to characterize the complexities of estimating unbiased gene expression from a targeted panel and developed a solution using a new normalization procedure that allows for accurate comparisons of samples within cancer types. Furthermore, we verified that lowering the RNA input amount or changing the assay operator does not contribute to a large variation in the gene expression estimates; each only accounts for less than 10% of variance of the average gene when the assay is compared across biological samples. Conclusions: Creating a panel that achieved high reproducibility and accurate expression estimates of key immune response genes allowed us to accurately separate high and low TIL samples within squamous and adenocarcinoma samples, emphasizing the utility of the panel to biomarker immunotherapy research. *For Research Use Only. Not for use in diagnostic procedures.
PARP inhibitor combination therapy in desmoplastic small round cell tumors.
Authors: Mellado-Lagarde Marcia , Federico Sara Michele , Tinkle Christopher , Shelat Anang , Stewart Elizabeth 
Published: September 2018

e23212 Background: Desmoplastic small round cell tumor (DSRCT) is a rare but pernicious mesenchymal neoplasm that expresses the EWS-WT1 gene fusion transcript. It has similar histopathology to Ewing sarcoma (EWS). In previous work, we showed that addition of Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi) to the existing standard of care (SOC) therapy of irinotecan (IRN) and temozolomide (TMZ) was remarkably successful at treating mouse models of EWS, resulting in > 80% complete response compared to 100% mortality with SOC alone. EWS has high levels of the protein Schlafen-11 (SLFN11), a putative biomarker for defective DNA damage repair. The goal of this study is to determine whether DSCRT also expresses SLFN11, and whether high levels of the protein sensitize the tumor to PARPi as single-agent or in combination with other drugs and ionizing radiation. Methods: SLFN11 mRNA and protein levels were assessed by immunohistochemistry, quantitative PCR, Western blot, and immunofluorescence microscopy. Viability of the DSRCT cell line, JN-DSCRT-1, was measured using CellTiterGlo and the colony forming assay. Ionizing radiation (IR) was delivered using an orthovoltage irradiator calibrated to deliver graded doses of 0-16 Gy. Results: We found that SLFN11 was detected at high levels in several DSRCT patient tumor samples, and we confirmed that SLFN11 transcript and protein levels in JN-DSCRT-1were comparable to EWS cell lines. JN-DSCRT-1 demonstrated sensitivity to PARPi as single-agent or in combination with either the topoisomerase I inhibitor irinotecan or ionizing radiation comparable to EWS cell lines. To supplement our in vitro studies and to utilize more accurate models of the clinical disease, we developed orthotopic patient derived xenograft models (O-PDX) from three patients with DSCRT. Preliminary findings suggest that these O-PDX models maintain SLFN11 expression and recapitulate important aspects of DSRCT biology, including widespread dissemination of tumor in the abdominal cavity and characteristic cellular phenotype. Preclinical in vivo efficacy studies with PARPi combinations are in progress. Conclusions: Our work suggests that DSCRT expresses the SLFN11 biomarker and is sensitive to PARPi combination therapy.
Phase 1 multicenter trial of CUDC-907 in children and young adults with relapsed or refractory solid tumors, CNS tumors, and lymphoma.
Authors: Shulman David Stephen , Gustafson Clay , Vo Kieuhoa Tran , Fox Elizabeth , Muscal Jodi Ann , Supko Jeffrey G. , Place Andrew E. , Chi Susan N. , Shusterman Suzanne , Hanna Gina , O'Brien Jane , Ezrre Suzanne , Carlowicz Cecilia , London Wendy B. , DuBois Steven G. 
Published: September 2018

TPS10576 Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777.
A bi-shRNAfurin and GMCSF engineered autologous tumor cell immunotherapy vs. gemcitabine + docetaxel for Ewing sarcoma and with cryoablation in Ewing family tumors.
Authors: Anderson Peter Meade , Ghisoli Maurizio , Barve Minal A. , Gill Jonathan Benjamin , Wexler Leonard H. , DeAngulo Guillermo , Neville Kathleen , Manning Luisa , Wallraven Gladice , Senzer Neil N. , Birkhofer Martin , Nemunaitis John J. 
Published: September 2018

TPS11079 Background: Vigil, an immuno-stimulatory autologous cellular therapy, uses patient tumor cells transfected with a plasmid encoding genes for GM-CSF and furin (to down regulate TGFβ 1&2). A Phase I study in relapsed Ewing’s sarcoma. (N = 16) had one 9 month partial response and a two-year survival rate of 44% [1]. Rapid, durable systemic immune activation was seen in the majority of patients using an IFNƔ ELISPOT assay [2]. We seek to extend these early findings in a randomized Phase 2 study (NCT02511132). Methods: Following surgery (for Vigil manufacture), patients are randomized 1:1 to Vigil (1 x 107cells/ml by monthly intradermal injection), or to chemotherapy with gemcitabine 675mg/m2 IV D1 and D8 and docetaxel 75 mg/m2 IV D8 every 21 days. Key eligibility criteria include: Age > 2, histologically documented metastatic Ewing's, refractory or intolerant to ≥2 prior lines of chemotherapy, and availability of at least 4 doses of manufactured Vigil. Patients with bone only disease are ineligible. The primary objective is to compare the overall survival of patients treated with Vigil vs. chemotherapy. The sample size of 62 patients assumes a one-year survival rate of 25% in the chemotherapy group vs. 60% in the Vigil group, corresponding to a hazard ratio of 0.383 favoring Vigil. Results: As of January 2017, thirteen patients have been randomized at 10 centers in the U.S. The design allows for reduction in disease burden prior to surgery using modalities like SBRT and interventional radiology. Toxicity of Vigil has been low compared to chemotherapy. Time to disease progression is being assessed in patients who crossover to Vigil after progressing on chemotherapy. Systemic control of metastatic lesions using cryoablation is also being assessed in other patients (e.g. DSRCT liver metastases) using a separate IND. Conclusions: Although associated with systemic immune activation, additional means to reduce disease burden such as SBRT and cryoablation can possibly improve patient health and augment Vigil efficacy. References: 1.Ghisoli M, Barve M, et al. Mol Ther. 2016 Apr 25 2. Oh J, Barve M, et al. Gynecologic Oncology 2016; 143: 504–510. Clinical trial information: NCT02511132.
A randomized, double-blind, placebo-controlled, phase III study of crenolanib in advanced or metastatic GIST patients bearing a D842V mutation in PDGFRA: The CrenoGIST study.
Authors: Blay Jean-Yves , Heinrich Michael C. , Hohenberger Peter , Casali Paolo Giovanni , Rutkowski Piotr , Serrano-Garcia Cesar , Jones Robin Lewis , Hall Kirsten Sundby , Eckardt John Randall , von Mehren Margaret 
Published: September 2018

TPS11080 Background: Activating mutations in the kinase domain of PDGFRA account for 10-15% of GIST. The most common PDGFRA mutation reported is D842V, which is known to confer resistance to imatinib and sunitinib. Currently, there is no approved treatment for GIST patients carrying such mutation. Cassier PA et al. showed that patients with D842V mutated GIST had a short median progression free survival (PFS) of 2.8 months with first line imatinib and 2.1 months with second line (2012 Clin Cancer Res). Crenolanib is a highly selective PDGFRA and FLT3 inhibitor with nanomolar activity against PDGFRα D842V mutation. In a previous dose-finding study, crenolanib showed a 31% clinical benefit rate with 2 pts achieving PR and 3 pts maintaining SD (total evaluable: 16 pts) in heavily pretreated GIST patients harboring the PDGFRA D842V mutation. In this study, 35% patients stayed on study for at least 7 months despite 80% patients having progressed after prior imatinib (15 pts), sunitinib (7 pts), dasatinib (5 pts), sorafenib (4 pts), nilotinib (2 pts), and regorafenib (2 pts). Therefore, a phase III trial has been initiated to further confirm the clinical activity of crenolanib in patients with PDGFRA D842Vmutation. Methods: This randomized phase III study will enroll adult subjects with histologically or cytologically confirmed advanced or metastatic GIST with a PDGFRA D842V mutation. Prior treatment with TKI is allowed. Approximately 120 subjects will be randomized in a 2:1 ratio to receive either crenolanib 100 mg or matching placebo orally 3 times daily in combination with best supportive care. Randomization will be stratified by prior tyrosine kinase inhibitor exposure and ECOG performance status. The primary objective is PFS; key secondary objectives include OS. A formal interim analysis is planned after approximately 50 subjects have met the primary outcome. This study is already opened in the US, France, Norway, and Poland, and will soon be opened in Germany, Italy, Spain, UK and Asia. NCT02847429; EudraCT: 2015-000287-34 Clinical trial information: NCT02847429.
Tappas: An adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (AAS).
Authors: Jones Robin Lewis , Attia Steven , Mehta Cyrus R. , Liu Lingyun , Sankhala Kamalesh Kumar , Robinson Steven Ian , Ravi Vinod , Penel Nicolas , Stacchiotti Silvia , Tap William D. , Alvarez Delia , Yocum Richard , Theuer Charles P. , Maki Robert G. 
Published: September 2018

TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.
A phase II randomized study to compare abemaciclib plus trastuzumab with or without fulvestrant to standard of care chemotherapy plus trastuzumab in hormone receptor positive, HER2-positive advanced breast cancer (monarcHER).
Authors: Tolaney Sara M. , Bourayou Nawel , Goel Shom , Hossain Anwar , Andre Fabrice 
Published: September 2018

TPS1109 Background: Inhibition of CDK4 in preclinical models, demonstrated efficacy in HER2+ breast cancer and enhanced activity of HER2-targeted therapy suggesting a crosstalk between HER2 signaling and the cyclin D/CDK4 signaling pathway in which CDK4 & CDK6 inhibitors may re-sensitize resistant tumors to HER2 blockade.Abemaciclib is a selective inhibitor of CDK4 & CDK6 inhibitor that demonstrates single-agent anti-tumor activity on a continuous dosing schedule in women with hormone receptor positive (HR+) advanced breast cancer. Triple regimens with abemaciclib have been tolerable. Methods: monarcHER is an ongoing Phase 2, open-label, study in postmenopausal women with HR+, HER2+ locally advanced or metastatic breast cancer. Eligible patients (pts) are those previously treated with ≥2 HER2-directed therapies in advanced disease setting; T-DM1 and a taxane in any disease setting; no prior treatment with fulvestrant or any CDK4 & CDK6 inhibitor or with ECOG PS ≤1; LVEF ≥50%; no visceral crisis and no CNS metastases that are untreated, symptomatic or requiring steroids. Pts are randomized 1:1:1 to Arm A (abemaciclib [150mg PO Q12H] plus trastuzumab [IV infusion Q3 weeks] plus fulvestrant [IM injection on D1, 15, 29 then Q4 weeks]), Arm B (abemaciclib plus trastuzumab), or Arm C (trastuzumab plus SOC single-agent chemotherapy of physician’s choice); stratified based on number of prior systemic regimens (excluding single agent endocrine therapy) and disease status (measurable vs nonmeasurable). The primary objective evaluates investigator-assessed progression-free survival (PFS). Secondary objectives include overall survival, objective response rate, duration of response, disease control rate, clinical benefit rate, safety and tolerability, efficacy, health outcomes and pharmacokinetics. Analysis is planned at 165 PFS events, providing ≥80% power to detect superiority of Arm A and Arm B over Arm C, assuming a hazard ratio of 0.67 at a one-sided alpha of 0.10. First pt visit occurred in May 2016; with a target enrollment of 225 pts. Contact information: 1-877-CTLILLY (1-877-285-4559) Clinical trial information: NCT02675231.