bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT017: A Phase Ib of a combination of two chimeric (Trastuzumab-like and Pertuzumab-like) HER-2 B cell peptide vaccine emulsified in ISA 720 and nor-MDP adjuvant in patients with advanced solid tumors
Authors: Bekaii-Saab Tanios , Wei Lai , Wesolowski Robert , Ahn Daniel , Wu Christina , Lustberg Maryam , Mortazavi Amir , Ramaswamy Bhuvaneswari , Overholser Jay , Kaumaya Pravin 
Published: August 2019

Abstract
Background: HER-2 is a transmembrane receptor that is overexpressed in multiple epithelial tumors. We have previously shown that a first generation HER-2 B-cell peptide vaccine targeting epitopes (628-647) and (316-339) was safe and relatively active. We recently developed a novel B-cell epitope specific vaccine (HER-Vaxx) consisting of epitopes derived from the extracellular domain of HER-2 that correspond to amino acid sequences 597-626 (pertuzumab binding site) and 266-296 (trastuzumab binding site).
Methods: This first-in-human Phase 1b study evaluated the safety, optimal immunologic/biologic dose (OID/OBD) and immunogenicity of HER-Vaxx. Using a 3+3 dose escalation design, 3 patients (pts) were treated at each dose level (DL). If &lt;2 pts experience dose-limiting toxicity (DLT), we required an additional 3 pts to be entered at that DL for OID/OBD assessment (defined as the dose level inducing a strong immunogenic response for 5 out of 6 patients). We also required that at least 6 patients at each DL to receive 3 inoculations of the combination vaccines at 3-week intervals and that &lt; 2 of the 6 pts experience DLT before dose escalation. DLs were 1.0 mg (DL1), 1.5 mg (DL2), 2.0 mg (DL3) and 2.5 mg (DL4) of each peptide. Each dose contained 0.025 mg of n-MDP.
Results: 49 patients with metastatic and/or recurrent solid tumors and a median of 4 prior lines of chemotherapy received at least one inoculation of HER-vaxx. Common related toxicities include injection site reactions (56% grade 1/2 and 5% grade 3/4). There were no DLTs. The OID/OBD was found to be DL 2 (1.5 mg of each peptide vaccine).A total of 28 patients received ≥ 3 vaccinations including 2 with a partial response and 14 with stable disease. Of those, 6 patients received at least one 6-month boost. The vaccine generated sustained humoral response eliciting HER-2 specific antibodies in the majority of responding patients.
Conclusion: We demonstrate that HER-Vaxx is well tolerated and able to generate sustained anti-HER-2 immune response. Given the promise, continuous development of the vaccine is ongoing at the suggested OBD in HER-2 overexpressing tumors.
Citation Format: Tanios Bekaii-Saab, Lai Wei, Robert Wesolowski, Daniel Ahn, Christina Wu, Maryam Lustberg, Amir Mortazavi, Bhuvaneswari Ramaswamy, Jay Overholser, Pravin Kaumaya. A Phase Ib of a combination of two chimeric (Trastuzumab-like and Pertuzumab-like) HER-2 B cell peptide vaccine emulsified in ISA 720 and nor-MDP adjuvant in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT017.
Abstract CT085: Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody
Authors: Condamine Thomas , Owens Sherry , Feldman Patricia , Motte-Mohs Ross La , Muth John , Sumrow Bradley , Moore Paul , Newton Robert 
Published: August 2019

Abstract
Background: The role of the PD-1 / PD-L1 axis in limiting T cell activity has been well established. Effective blockade of this pathway has been demonstrated to lead to an increase in T cell activity and to yield clinical activity in cancer patients. INCMGA00012 is a humanized IgG4 monoclonal antibody that binds to human PD-1 and blocks its interaction with PD-L1/PD-L2. This therapeutic antibody has demonstrated acceptable tolerability with evidence of clinical activity in a phase 1 study in patients with solid tumors (NCT03059823). Pharmacodynamic markers demonstrating biological activity of INCMGA0012 were assessed in samples collected during the study.
Methods: Blood samples were collected at baseline and at various time points following treatment from patients receiving doses of either 3mg/Kg (Q2W) in the tumor-specific expansion cohort or a flat-dose of 500 or 750mg (Q4W) in the tumor-agnostic expansion cohort. Receptor occupancy was measured on circulating T cells by flow cytometry and serum cytokine levels were measured using either a proximity extension assay or immunoassays. In addition, circulating immune cell phenotyping was analyzed using flow cytometry and PBMC functionality evaluated using ex-vivo re-stimulation.
Results: All tested doses of INCMGA0012 evaluated demonstrated a full saturation of the PD-1 receptor at trough on circulating CD4 and CD8 T cells. In all tested cohorts, an increase in serum CXCL9 and CXCL10 was observed following infusion with INCMGA0012. Moreover, an increase in the proliferation of circulating T cells was observed on treatment compared to baseline. Concurrently, following ex vivo re-stimulation, T cells isolated from peripheral blood mononuclear cells demonstrated an increased capacity to secrete cytokines.
Conclusion: These results provide evidence that INCMGA0012 is biologically active and leads to an increase in IFNγ-related protein levels (i.e. CXCL9 and CXCL10) and in T cell proliferation. The clinical activity of INCMGA0012 is undergoing further evaluation in several indications, including endometrial cancer, Merkel cell carcinoma and squamous carcinoma of the anal canal. Several combination studies have also been initiated.
Citation Format: Thomas Condamine, Sherry Owens, Patricia Feldman, Ross La Motte-Mohs, John Muth, Bradley Sumrow, Paul Moore, Robert Newton. Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT085.
Abstract CT161: A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Einstein David J. , Choudhury Atish , Saylor Philip , Werner Lillian , Erlander Mark , Ridinger Maya , Bubley Glenn 
Published: August 2019

Abstract
Background: mCRPC remains a leading cause of cancer-related deaths worldwide. Although abi increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. PLK1, a serine/threonine kinase, is a master regulator of cell-cycle progression and is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In Phase I testing, onvansertib demonstrated a manageable safety profile, with transient hematologic effects as its most prominent, yet reversible, toxicity.
Methods: The goal of this Phase II study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients are enrolled at time of PSA progression while on standard abi and treated with onvansertib (24 mg/m2 orally on days 1-5 of a 21-day cycle) plus abi (administered orally and continuously once daily with prednisone) until time of radiographic or symptomatic progression. The safety lead-in of 3 subjects showed no dose-limiting toxicities or new toxicities from the combination of onvansertib with abi. A 29-patient expansion phase is ongoing, with 11 patients enrolled as of January 2019. With 32 patients, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if &lt;2 of the first 13 patients achieve disease control. Toxicity and PSA levels are monitored during treatment. Exploratory analyses include quantification of circulating tumor cells, evaluation of PLK1 inhibition in vivo and evaluation of predictive genomic biomarkers in circulating tumor DNA, such as alterations in oncogenes and tumor suppressors.
Citation Format: David J. Einstein, Atish Choudhury, Philip Saylor, Lillian Werner, Mark Erlander, Maya Ridinger, Glenn Bubley. A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT161.
Abstract CT165: Phase II open label trial of minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer
Authors: Propper David , Han Haiyong , Hoff Daniel Von , Borazanci Erkut , Reya Tannishtha , Ghergurovich Jonathan , Pshenichnaya Irina , Antal Corina , Condjella Rachel , Sharma Shreya , O'Dwyer Peter , Littlewood Trevor , Patel Hitendra , Saluja Ashok , Velagapudi Mohana , Yang Lifeng , Downes Michael , Evans Ronald , Evan Gerard 
Published: August 2019

Abstract
BackgroundTriptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer cell compartments. In the epithelial tumour compartment, triptolide down-regulates key transcription factors such as c-MYC. In the phase I clinical trial of Minnelide™ significant activity in highly refractory metastatic pancreatic carcinoma was observed. Hence we undertook this study in patients with chemotherapy refractory metastatic PDAC.
MethodsEligibility criteria include stage IV PDAC that has progressed on standard chemotherapy, Karnofsky performance status ≥ 70%, and measurable disease. Planned sample size is up to 35 patients with interim analysis after the first 18 evaluable patients, aiming for at least a 20% difference in DCR (10% v 30%). Minnelide™ 0.67 mg/m2 is administered intravenously over 30 minutes on days 1-21, followed by a 7 day rest period in a 28 day cycle. Exploratory objectives include: analysis of tumor texture on radiologic scans as a non-invasive biomarker for response, as well as analyses of paired tumour biopsies for changes in immune cell infiltration, stromal activation, chromatin accessibility, phopshoproteomics and metabolism. # NCT03117920The trial opened 4/2017 and as of 12/2018, 18 patients have been treated. Supported by SU2C, Cancer Research UK, Lustgarten Foundation
Citation Format: David Propper, Haiyong Han, Daniel Von Hoff, Erkut Borazanci, Tannishtha Reya, Jonathan Ghergurovich, Irina Pshenichnaya, Corina Antal, Rachel Condjella, Shreya Sharma, Peter O'Dwyer, Trevor Littlewood, Hitendra Patel, Ashok Saluja, Mohana Velagapudi, Lifeng Yang, Michael Downes, Ronald Evans, Gerard Evan. Phase II open label trial of minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT165.
Abstract DDT01-02: Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor
Authors: Goldberg Frederick W. , Cadogan Elaine , Finlay Raymond , Montoya Antonio Ramos , Beattie David , Lamont Gillian , Fallan Charlene , Fok Jacqueline , Vazquez-Chantada Mercedes , Barratt Derek , Dean Emma , Norris Jane , Campbell Andrew , Cronin Anna , Harding Joanna , Ting Attilla , Hollingsworth Simon , Davies Barry 
Published: August 2019

Abstract
DNA-dependent kinase (DNA-PK) plays an important role in the cellular response to DNA damage through the detection and repair of double strand breaks, and is a critical component of the DNA damage response (DDR). Double strand breaks can be induced by a range of agents, including chemotherapy, radiation or PARP inhibitors such as olaparib (Lynparza), and thus a DNA-PK inhibitor is likely to sensitise to these agents. DNA-PK inhibitors may also be effective as monotherapy in tumours with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. Our screening strategy focussed on identifying hits with good selectivity versus structurally related kinases. Significant improvements were made to permeability, metabolic stability and PK properties, whilst improving potency and selectivity with a structure-guided approach. This optimisation resulted in AZD7648, which is a potent inhibitor of DNA-PK (0.6 nM in biochemical assay, 89 nM in A549 cells) and &gt;100x selective against 396 other kinases in a Thermofisher selectivity panel. In addition, AZD7648 has good crystalline solubility, metabolic stability and predictable pharmacokinetics in preclinical species. In murine xenograft models, PD was assessed using pRPA (S4/8) and was potently inhibited (in vivo IC50 = 52 nM). Tumour growth inhibition was observed with AZD7648 as monotherapy, and regressions were observed in combination with either olaparib or radiation. The efficacy observed when combining AZD7648 with olaparib was correlated to free cover over the in vivo IC90. AZD7648 is a potent and highly selective DNA-PK inhibitor, with good crystalline solubility, permeability and metabolic stability, good bioavailability and predictable pharmacokinetics in preclinical species, and potent knockdown of pRPA and regressions in murine xenograft models when combining with olaparib or radiation. These features make AZD7648 a suitable clinical candidate, and clinical studies evaluating AZD7648 as a potential cancer treatment are planned in 2019.
Citation Format: Frederick W. Goldberg, Elaine Cadogan, Raymond Finlay, Antonio Ramos Montoya, David Beattie, Gillian Lamont, Charlene Fallan, Jacqueline Fok, Mercedes Vazquez-Chantada, Derek Barratt, Emma Dean, Jane Norris, Andrew Campbell, Anna Cronin, Joanna Harding, Attilla Ting, Simon Hollingsworth, Barry Davies. Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr DDT01-02.
Abstract LB-037: A novel zebrafish platform for deciphering the mutations co-operation in driving acute myeloid leukaemia
Authors: Cheng Yik Ling Bowie , He Bai Liang , Wang Dan Dan , Leung Yu Hung Anskar 
Published: August 2019

Abstract
Background and Objectives: Acute myeloid leukaemia (AML) is a highly genetically heterogenous disease. Patients carry unique genetic mutational profile that affect their clinical outcome. Remarkably, there are common patterns of co-occurring mutations, indicating their potential cooperativity in driving leukaemia. This project presents a novel zebrafish platform that allows quick and traceable evaluation of the impact of different genetic mutation combinations on leukemogenesis and drug response, paving the way for personalized medicine.
Experimental Procedures and Results: Zebrafish embryos were co-injected with combination of mutations FLT3 ITD with IDH2R140Q, IDH2R172K, IDH1R132H and DNMT3AR882H), and their effect on the expression pattern and intensity of different myeloid lineage markers including pu.1 (myeloid progenitor), mpo (macrophage), c-myb (haematopoietic stem cell; HSC) and Sudan Black B staining (neutrophils or granulocytes) were evaluated. Consistent with TCGA database, which showed FLT3 ITD mutation only co-occurred with IDH2R140Q or DNMT3AR882H, overexpression of FLT3 ITD and IDH2R140Q in zebrafish embryo promoted expansion of myeloid progenitors and granulocytes, while co-expression of FLT3 ITD and DNMT3AR882H promoted expansion of HSCs and granulocytes. No combinatory effects were observed between FLT3 ITD and IDH2R172K or IDH1R132H. To establish a zebrafish-based platform for predicting differential drug responses for unique mutational profiles, zebrafish embryos were injected with FLT3 ITD and IDH2R140Q and a list of FDA approved and preclinical drugs were examined for their efficacy on rescuing FLT3 ITD/IDH2R140Q-induced myeloid expansion. Although FLT3 ITD inhibitor was able to rescue FLT3 ITD-induced myeloid expansion, the effect was alleviated if FLT3 ITD and IDH2R140Q were co-expressed, indicating specific mutation patterns affected drug responses. To further validate our findings and study the long-term effect of mutation combinations, transgenic fish lines with FLT3 ITD/IDH2R140Qand FLT3 ITD/IDH2R172K under Runx1 promoter (HSC lineage) were established with Tol2 transgenesis. At 6 months of age, Tg(Runx1:FLT3 ITD, IDH2R140Q) showed increased percentage of myeloid precursors compared to WT and single mutant group.
Conclusion: Our result show that zebrafish can serve as an effective platform to study the cooperative effect of mutations in acute myeloid leukaemia and predict a better option for patients carrying unique genetic mutational profiles, paving the way for personalized medicine.
Citation Format: Yik Ling Bowie Cheng, Bai Liang He, Dan Dan Wang, Yu Hung Anskar Leung. A novel zebrafish platform for deciphering the mutations co-operation in driving acute myeloid leukaemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-037.
Abstract LB-100: HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function
Authors: Wang Chengcheng , Wu Chen , Lin Dongxin , Zhao Yupei 
Published: August 2019

Abstract
BACKGROUND: Genome-wide association studies (GWAS) have identified several genetic regions associated with risk of pancreatic ductal adenocarcinoma (PDAC) while the underlying mechanisms remain largely unknown. This study investigated the functions of genes in these genetic regions and their roles as potential biomarkers or therapeutic targets for PDAC.
METHODS: We reanalyzed our previous GWAS data based on referring the 108 risk loci reported in published PDAC GWAS to seek for all susceptibility genes in the Chinese population and found 44 potential risk genes. A siRNA library was used to silence these genes in PDAC cell lines and the malignant phenotypes were examined by using a high content screen method followed by a series of functional assays.
RESULTS: Among the 44 genes, HNF4G was the top one who’s silencing significantly repressed PDAC cell migration and invasion. Functional assays showed that HNF4G regulates cell-cell junction pathway, which may be the underlying mechanism for its action. HNF4G was upregulated by SMAD4 loss of function and frequently overexpressed in PDACs. PDAC cell metastasis promoted by the overexpression of HNF4G could be suppressed by metformin, and this effect was seen only in PDAC cells with SMAD4 loss of function, resulting in heterogeneous vulnerability of PDAC to the drug. CONCLUSION: HNF4G overexpression might result in metformin sensitivity in PDAC with SMAD4 loss of function and thus represent as a potential therapeutic target.
Citation Format: Chengcheng Wang, Chen Wu, Dongxin Lin, Yupei Zhao. HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-100.
Abstract LB-226: Utilizing 486 gene assay on a NGS platform to validate guideline-adherent tumor mutational burden (TMB) module to calculate TMB
Authors: AHLUWALIA PANKAJ K. , MONDAL ASHIS , ANANTH SUDHA , HENEIDI SALEH , KOTA VAMSI , KOLHE RAVINDRA 
Published: August 2019

Abstract
Introduction: The quantification of TMB has emerged as a highly promising biomarker in predicting immunotherapeutic responses. The application of whole exome sequencing to measure TMB has shown to predict response to immunotherapy. Multiple studies have shown that TMB quantification using large panels are comparable to whole exome sequencing and are more practical for implementation in clinical care. The QIAseq TMB panel is a new NGS assay designed to detect genetic alterations in 486 genes, along with MSI and TMB score. Methods: The validation was guided by the joint consensus recommendation for validation of NGS assays by the AMP & CAP and NYSDOH. The validation included evaluations of precision, analytic sensitivity, analytic specificity, accuracy, reportable range, and reference range for TMB. DNA from of 60 samples which were characterized on Foundation CGP assay were used during the validation. Libraries were prepared using the QIAseq TMB panel kit and sequenced on NextSeq 550. The TMB module used for calculation of TMB in this validation was designed and developed by QIAGEN. TMB was calculated as the number of somatic mutations (SNVs and Indels only) per megabase (Mb) of the target region (1.2 Mb for QIAseq TMB panel). Results: In silico analysis using the TCGA data by QIAGEN QCI pipeline showed that the QIAseq TMB panel estimates TMB at a high level of concordance with whole exome sequencing (WES). The data show a high correlation (r2 = 0.98) between the TMB values determined using WES data and TMB using the QIAseq TMB panel data. Our validation data shows significant correlation (r2 = 0.94) among TMB values on the QIAseq panel and Foundation one CGP. Conclusions: In this validation we demonstrate that the QIAseq TMB assay can be used to reliably predict TMB across a wide range of cancer types using the QIAGEN QCI TMB module. Our lab’s experience provides an example for others that may wish to implement TMB testing by NGS on a comprehensive panel.
Citation Format: PANKAJ K. AHLUWALIA, ASHIS MONDAL, SUDHA ANANTH, SALEH HENEIDI, VAMSI KOTA, RAVINDRA KOLHE. Utilizing 486 gene assay on a NGS platform to validate guideline-adherent tumor mutational burden (TMB) module to calculate TMB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-226.