bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipegfilgrastim: A long-acting, once-per-cycle, glycopegylated recombinant human filgrastim.
Authors: Scheckermann Christian , Schmidt Karsten , Abdolzade-Bavil Afsaneh , Allgaier Hermann , Mueller Udo W. , Shen Wenyan David , Liu Patrick 
Published: March 2020

e13548 Background: Lipegfilgrastim is a once-per-cycle fixed-dose glycoPEGylated granulocyte-colony stimulating factor (G-CSF) under development for the prevention of severe neutropenia in cancer patients receiving chemotherapy (CTx). PEGylation of a molecule extends its half-life in the body, requiring less frequent dosing and allowing for administration of G-CSF once per CTx cycle, making treatment potentially less expensive and enhancing patient compliance and safety. Briefly, traditional PEGylation methods use chemical conjugation through reactive groups on amino acids, which may reduce protein activity and result in non-uniform chemical and pharmaceutical properties. Here, we describe a highly site-specific GlycoPEGylation technology for site-directed PEGylation and summarize preclinical findings compared with pegfilgrastim (Neulasta). Methods: Glycosylation sequon scanning was used to identify the glycoPEGylation site with least impact on protein activity. E. coli-expressed G-CSF was selectively glycosylated at natural O-glycosylation sites and a polyethylene glycol (PEG) sialic acid derivative attached using a sialyltransferase (glycoPEGylation technology). Ligand binding affinity was assessed using the BIACORE 3000 system. Biologic activity of lipegfilgrastim was assessed in an NFS-60 cell line proliferation assay vs filgrastim and pegfilgrastim. PK and PD properties were studied in healthy and neutropenic animal models. Results: GlycoPEGylation produces long-acting G-CSF with improved PK profiles. In vitro, lipegfilgrastim had binding affinity and specific activity comparable to pegfilgrastim, and both were lower than non-PEGylated filgrastim. Comparable increases in leukocytes, neutrophilic granulocytes, and monocytes were seen with lipegfilgrastim and pegfilgrastim in rats and monkeys and were consistent with the effects expected for a long-lasting G-CSF. Conclusions: GlycoPEGylation technology platform is used to produce lipegfilgrastim – a novel, biologically active G-CSF with greater structural homogeneity and comparable pharmacologic properties to conventionally PEGylated G-CSFs.
Balugrastim: A long-acting, once-per-cycle, recombinant human albumin-fusion filgrastim.
Authors: Pukac Laurie , Barash Steven , Avisar Noa , Allgaier Hermann , Bock Jason , Mueller Udo W. , Shen Wenyan David 
Published: March 2020

e13551 Background: Balugrastim is a once-per-cycle fixed-dose genetic fusion protein composed of human serum albumin (HSA) and granulocyte colony-stimulating factor (G-CSF) in development for prevention of severe neutropenia in cancer patients receiving chemotherapy. Albumin fusion is a clinically validated technology that extends product half-life, allowing for infrequent dosing, better tolerability, lower cost, and improves drug design, potentially lowering immunogenicity risk. Here, we describe the technology used to produce balugrastim and summarize preclinical findings compared with pegfilgrastim (Neulasta). Methods: Design and production of balugrastim was described previously (Halpern et al. Pharmaceut Res 2002;19:1720−1729). Biologic activity of balugrastim was assessed in an NFS-60 cell line proliferation assay vs filgrastim and pegfilgrastim. PK and PD properties were studied in healthy and neutropenic animal models. Results: Albumin fusion produces a long-acting G-CSF with comparable pharmacologic properties to pegfilgrastim. In vitro, balugrastim had binding affinity and cell proliferation activity comparable to pegfilgrastim, and both were lower than non-PEGylated filgrastim on a molar basis. Overall increases in leukocytes, neutrophilic granulocytes, and monocytes were dose dependent and consistent with the effects expected for a long-acting G-CSF with some variation based on the specific animal model used. A single balugrastim dose in BDF1 mice elicited a dose-dependent increase in peripheral granulocytes and mobilized hematopoietic progenitor cells. In cynomolgus monkeys, balugrastim caused an increase in peripheral neutrophils similar to pegfilgrastim, with higher responses after 2nd, 3rd, and 4th doses. In mice, balugrastim had shorter terminal half-life and mean residence time, and faster clearance than pegfilgrastim. In monkeys, terminal half-life of balugrastim was slightly longer than pegfilgrastim. Conclusions: An albumin fusion technology platform was used to produce balugrastim – a novel, biologically active albumin G-CSF fusion protein with greater structural homogeneity and comparable pharmacologic properties to conventionally PEGylated G-CSFs.
Clinical safety of tbo-filgrastim in chemotherapy-induced neutropenia: Integrated analysis of the phase III studies.
Authors: Engert Andreas , Buchner Anton , Mueller Udo W. , Bias Peter 
Published: March 2020

e13552 Background: Tbo-filgrastim is a granulocyte colony-stimulating factor (G-CSF) approved for use in the US as a biologic under BLA 351(a) for reducing duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia. Here, we report an integrated analysis of clinical safety data from three Phase III studies. Methods: Safety results from three Phase III studies in breast cancer (placebo-controlled), non-small cell lung cancer, and non-Hodgkin lymphoma were integrated. All safety variables were analyzed using descriptive statistics. The incidence of treatment-emergent adverse events (TEAEs) was compared between treatment groups using Fisher's exact test (2-sided P-values). Changes in laboratory parameters from baseline were compared between the tbo-filgrastim and filgrastim treatment groups using the Wilcoxon test. Results: In the integrated analysis of CTx Cycle 1, 80.2% of 677 patients experienced a TEAE; 16.7% of these were related to study drug. The most commonly reported TEAEs were nausea, alopecia, neutropenia, diarrhea, asthenia, and vomiting, and most due to concomitant CTx. The most commonly reported drug-related TEAEs were bone pain (3.4%), diarrhea (2.2%), asthenia (2.2%), myalgia (1.9%), arthralgia (1.5%), headache (1.2%), and pyrexia (1.0%), all of which are characteristic of G-CSFs. Five patients had serious drug-related TEAEs; none caused reductions in the dose of study drug or scheduled CTx. There were 11 deaths across studies; none was considered drug related. There were no clinically significant differences between tbo-filgrastim and filgrastim in the overall incidence of deaths, serious or severe TEAEs, discontinuations due to TEAEs, or in laboratory safety variables. In all cycles of CTx, the most commonly reported TEAEs in patients treated with tbo-filgrastim correlated with those of the reference filgrastim. Conclusions: Tbo-filgrastim is safe and well tolerated in breast cancer, non-small cell lung cancer, and non-Hodgkin lymphoma patients undergoing CTx, with a safety profile similar to that of the reference filgrastim. Clinical trial information: 2004-001452-36, 2004-001450-84, 2004-001449-13.
An examination of crizotinib activity in human tumor primary culture micro-spheroids isolated from patients with advanced non-small cell lung cancer.
Authors: Nagourney Robert Alan , Ou Sai-Hong Ignatius , Bernard Paula J , Francisco Federico R , Evans Steven S 
Published: March 2020

e13558 Background: The amino-pyridine, Crizotinib (Criz) (PF02341066, Xalkori), active against c-MET is an inhibitor of anaplastic lymphoma kinase (ALK). Identification of ALK-gene rearrangement in NSCLC led to clinical trials & FDA approval. Recognition of ROS-1 mutations as Criz targets provided additional therapy options. ALK mutations found in NSCLC also occur in lymphoma, neuro & myofibroblastic tumors but may participate in the oncogenesis of other tumors. Methods: We used ex vivo analysis of programmed cell death (EVA/PCD) (Nagourney, R. Curr Treat. Op Oncol, 2006) to examine Criz activity in human tumor 1°culture micro-spheroids, from 60 surgical specimens, with a focus on NSCLC. Using metabolic (ATP-content; mitochondrial) & morphologic (membrane integrity) endpoints, dose response curves were interpolated to LC50 values for comparison of activity by patient & tumor type. Patients were screened for ALK & ROS-1 by FISH. Results: ALK (+) tumors reveal lower LC50’s (3.4 uM) vs. ROS-1 (+) (11.5 uM), despite clinical responses in both groups. A Criz-responding patient, at 2nd biopsy for progression, reverted to Criz-resistance but developed collateral sensitivity to cytotoxics that provided durable response. Despite FISH (-), a 39 y/o nonsmoker male, revealed exquisite sensitivity to Criz by repeat EVA/PCD. At our insistence, FISH conducted at a 2nd reference lab correctly identified ALK(+) qualifying for Criz, to which he responded, now at year 2. Using low LC50 as a phenotypicmarker of Criz responsiveness, we identified activity in an extremely rare pediatric sarcoma patient. When, secondarily screened, patient found ALK (+), followed by rapid objective response to Criz. Conclusions: Primary culture analyses provide insights into Criz activity including ALK (+) vs. ROS-1(+), individual patient response profiles, and the identification of Criz candidates, who might otherwise not be screened for sensitizing mutations. By capturing human tumors in their “native” state EVA/PCD offers opportunities to study Criz for unrecognized targets and analyze novel strategies including synergy & sequence dependence, less readily examined with genomic platforms.
Preclinical toxicology studies with Y15, a novel focal adhesion kinase (FAK) inhibitor.
Authors: Cance William G. , Curtin Leslie , Buitrago Sandra , Golubovskaya Vita 
Published: March 2020

e13561 Background: Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors and plays a major role in survival signaling. Recently, we developed a FAK scaffolding inhibitor, Y15 that targeted the main FAK autophosphorylation site (Y397) and had high efficacy in blocking tumor growth in many xenograft mice models. We performed a small animal toxicology study of Y15 and detected the maximal tolerated dose of this drug in mice. Methods: The toxicology study was performed in CD-1 albino [Hsd:ICR(CD-1)] mice with Y15 inhibitor delivered either by intraperitoneal injection (IP) or by oral delivery. Clinical chemistry data were collected by Hemagen Analyst II automatic Chemistry analyzer. In addition, hematology, body weight, mortality, and histopathology on different organs were analyzed in all mice. Results: We delivered Y15 by IP injection at 15 (low), 30 (medium) and 45 mg/kg (high) doses daily for 5 days/week during a 28 day study, or orally by gavage at 100 and 200 mg/kg daily during a 7 day study. The maximal tolerated dose by IP during 28 day study was 30 mg/kg. The maximal tolerated dose during single oral dose administration was 200 mg/kg and 100 mg/kg during 7 day study. Y15 did not cause any mortality or statistically significant differences in the body weight at 30mg/kg IP delivery during a 28-day study and at 100 mg/kg by oral delivery during a 7 day study. There were no significant clinical chemistry changes in alkaline phosphatase, gamma glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, amylase, blood urea nitrogen, glucose, phosphorus, calcium, albumin, cholesterol, creatine kinase, total bilirubin, total protein and globulin. Finally, no significant histopathological changes were observed by necropsy in different organs at 30 mg/kg by IP and at 100 mg/kg dose by oral delivery. Conclusions: The Y15 FAK autophosphorylation inhibitor is well tolerated in mice and caused no significant toxicity by IP and oral delivery, suggesting it is a promising candidate for further large animal toxicology study prior to human trials.
Pruritus in patients treated with targeted cancer therapies: Systematic review and meta-analysis.
Authors: Ensslin Courtney J. , Rosen Alyx C. , Wu Shenhong , Lacouture Mario E. 
Published: March 2020

e13571 Background: Pruritus is a disabling symptom that has been anecdotally described in patients treated with targeted cancer therapies, and reports on its incidence vary. The overall risk to develop pruritus in these patients has not been systematically ascertained. We conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing pruritus among patients treated with targeted therapies. Methods: Databases from PubMed and Web of Science from January 1998 until July 2012 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2012 were searched to identify relevant studies. The incidence and relative risk (RR) of pruritus were calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies. Results: Of 5,065 studies initially identified, a total of 20,532 patients from 144 studies were included for analysis. The summary incidences of all-grade and high-grade pruritus were 17.4% (95% confidence interval (CI): 16.0%-19.0%) and 1.4% (95% CI: 1.2%-1.6%). From randomized controlled trials, patients treated with targeted therapies had a significantly increased risk of developing all-grade pruritus, with an overall RR of 2.59 (95% CI: 2.03-3.30, p<0.001); there was a significant variation among different classes of drugs (P<0.001). Conclusions: There is a significant risk of developing pruritus in cancer patients receiving targeted therapies. In order to prevent suboptimal dosing and reductions in quality of life, these patients should be counseled and treated against this disabling event.
Time-dependent estimates of recurrence and survival in colon cancer: clinical decision support system tool development for adjuvant therapy and oncological outcome assessment.
Authors: Steele Scott , Bilchik Anton , Johnson Eric , Nissan Aviram , Peoples George Earl , Eberhardt John , Kalina Philip , Petersen Benjamin , Bruecher Bjoern L. D. M. , Protic Mladjan , Avital Itzhak , Stojadinovic Alexander 
Published: March 2020

e14500 Background: Unanswered questions remain regarding treatment efficacy in colon cancer (CC), especially those determining high-risk node-negative cohorts that may benefit from adjuvant therapy. We sought to evaluate the use of machine learning and classification modeling to estimate survival and recurrence in CC. Methods: We used the Department of Defense Automated Central Tumor Registry (ACTUR) to identify primary CC patients treated between January 1993 and December 2004. Cases with events or follow-up that passed quality control were stratified into one-, two-, three-, and five-year survival cohorts. ml-BBNs were trained using machine-learning algorithms and k-fold cross-validation, and receiver operating characteristic (ROC) curve analysis used for validation. Results: There were 5,301 cases stratified into cohorts. Survival cohort Areas-Under-the-Curve (AUCs) ranged from 0.85–0.90, positive-predictive-values (PPVs) for recurrence and mortality ranged from 78-84% and negative-predictive-values (NPVs) from 74-90%. Cross-validation showed that the ml-BBNs produce robust individual estimates of recurrence (p<0.001) and mortality (p<0.001) based on readily available clinical-pathological information in the context of adjuvant chemotherapy. Conclusions: Tumor registry data and machine-learned Bayesian Belief Networks produce robust classifiers. These Clinical Decision Support System tools yield clinically relevant estimates of outcomes that may assist clinicians in treatment planning.
Surgical resection of liver metastases and survival outcomes in real-life for metastatic colorectal cancer (mCRC) patients treated in front-line with cetuximab (CTX): The EREBUS cohort.
Authors: Smith Denis Michel , Sa Cunha Antonio , Rouyer Magali , Noize Pernelle , Jove Jeremy , Bignon Emmanuelle , Le Monies Alise , Mitry Emmanuel , Francois Eric , Fourrier-Réglat Annie 
Published: March 2020

e14514 Background: CTX has demonstrated improved survival outcomes and resection rate in unresectable mCRC patients (pts) but little data is available from real-life use. Methods: EREBUS is a French multicentre (n=65) cohort that included pts with unresectable mCRC and wt KRAS initiating 1st-line CTX in 2009 and 2010, and followed 12 months. An expert committee validated baseline resectability and resection results. Resection rates and survival outcomes were described according to metastases site: liver-only, liver-not exclusively, other. Results: 389 pts were included: 37.8% liver-only metastases, 38.3% liver-not exclusively, 23.9% other. Baseline characteristics of the cohort: median age 64 yrs, 67.4% male, 77.9% ECOG=0-1, 55.5% primary tumor resection, 53% single metastatic site. Combined chemotherapy regimen were with irinotecan (56.6%) or oxaliplatin (38.2%). Median duration of CTX use was 4.8 months. 97 pts (24.9%, 95%CI: 20.6-29.2) had metastases resection; rates for liver-only: 36.7% (28.9-44.5), liver-not exclusively: 20.8% (14.3-27.3), other: 12.9% (6.9-21.5). Among them, 51.5% had radical resection with R0+/-radiofrequency (liver-only: 61.1% and liver-not exclusively: 32.3%), 11.3% R1+/-radiofrequency (liver-only: 16.7% and liver-not exclusively: 3.2%) and 9.4% missing metastases, 27.3%R2. 52.6% had post-operative complications (20.6% infection, 8.2% thromboembolic event, 8.2% other cardiovascular event, 3.1% death). Median PFS for the cohort was 9.7 months (8.6-10.5). In multivariate Cox analysis progression was independently associated with metastases site, liver-only: HR=1.93 (1.36-2.74), liver-not exclusively: HR=1.46 (1.06-2.02). The 1-yr OS probability was 71.3% (66.4-75.6) without any site difference. In Cox analysis, death was less likely in responders with or without metastases surgery: HR=0.26 (0.08-0.90) and HR=0.37 (0.21-0.63). Conclusions: This cohort shows that 1st-line CTX in wt KRAS mCRC allows a high proportion of metastases resection, particularly in liver-only. It also provides data on rarely studied mCRC pts (liver-not exclusively and other metastases).
Secondary resection in a general mCRC population with cetuximab-based first-line treatment: Interim analysis of the German noninterventional study ERBITAG.
Authors: Neumann Ulf P , Goehler Thomas , Reich Gernot , Schwerdtfeger Michael , Stuebs Patrick , Stenzel Karsten G , Overkamp Friedrich 
Published: March 2020

e14532 Background: Resection of liver and/or lung metastases (LM) are a potentially curative option for patients with mCRC. Cetuximab in combination with irinotecan- or oxaliplatin-based chemotherapy has shown to increase the resection rate of primarily unresectable LM in mCRC patients. After approval of cetuximab in Germany for first-line treatment of pts with unresectable mCRC, this noninterventional study was initiated to evaluate safety and efficacy of cetuximab in combination with various first-line chemotherapy regimens in patients with unresectable mCRC. Methods: We conducted an interim analysis of the first 124 fully documented pts to evaluate the response rate (RR) and resection rate of LM. Enrolment was restricted to pts with mCRC with proven KRAS wildtype mutation status without prior systemic treatment in the metastatic stage. Predefined endpoints were amongst others RR, LM resection rate, TTF, PFS, OS, and safety. Results: From May 2010 to May 2012 360 eligible pts were enrolled at 109 sites (75% office-based physicians), documentation for 124 was finalised (data cut-off for this analysis 03 May 2012) and evaluated. The median age was 68 [range 34-84] years, ECOG performance status was 0, 1, 2 in 29%, 60%, and 9% of pts, respectively, in 2% of pts ECOG performance status was missing. Resection rate was 18.5% (n=23) performed at 18 sites with 16.9% R0 resections (n=21). 42% of pts (n=52) had liver-limited disease (LLD). Resection rate in pts with LLD was 34.6% (n=18) with a 30.6% R0-resection rate (n=16). Median treatment duration from start of cetuximab-based therapy to resection of LM was 3.7 months [0.7-12.0]. Objective response rate was 46.8% (CR 4.8%, PR 41.9%) and 59.6% (CR 5.8%, PR 53.8%) for pts with LLD. Conclusions: In a clinical practice setting cetuximab-based first-line treatment of an unselected population with KRAS wildtype mCRC resulted in an R0-resection rate of 16.9% overall, and 30.6% for LLD pts. These data compare fairly well with data from clinical trials: CRYSTAL, OPUS, and CELIM.
Multimodality treatment combining chemotherapy, liver surgery, peritoneal resection and hyperthermic intraperitoneal chemotherapy (HIPEC) for metastatic colorectal cancer (mCRC) patients with synchronous liver metastases (LM) and peritoneal carcinomatosis (PC): A multicenter study of the French Association of Surgery.
Authors: Lo Dico Rea , Passot Guillaume , Elias Dominique , Lorimier Gerard , Quenet Francois , Pocard Marc 
Published: March 2020

e14534 Background: Pts with synchronous PC and LM are generally considered for exclusive systemic palliative chemotherapy only. Aggressive surgical approaches combining hepatectomy associated to peritoneal resection with curative intent remain controversial in such a setting and almost no data are available on such patients.The aim of this prospective cohort was to assess morbidity, mortality, disease-free survival (DFS) and overall survival (OS) of peritoneal and liver mCRC patients (pts) treated with an aggressive therapeutic approach combining surgical treatment of liver and peritoneal lesions followed by HIPEC. Methods: All patients registered in the French Association of Surgeryprospective database with PC and synchronous LM who had undergone cytoreductive surgery and LM resection followed by intraperitoneal chemotherapy were analysed. The primary endpoint was survival from the time of surgery. The following criteria were recorded and analyzed: sex, age, differentiation and localization of the primary tumor, lymph node involvement (pN+), peritoneal cancer index (PCI), completeness of cytoreduction of peritoneal carcinomatosis, number of associated liver metastases. Results: From 1993 to 2011, 101 pts with PC and LM were analyzed. After a mean follow-up of 25 months, the median OS and DFS, were respectively 24.9 and 9.5 months. Post-operative morbidity and mortality was 14.8 and 0%, respectively. In pts with a complete cytoreductive surgery OS was 29 months (n=), as compared to 4 months in pts (n=) with incomplete cytoreduction (p=0.0001). Rectal primary tumor, PCI of 13 or more, pN+ status, and more than 3 LM were not identified as independent factors for poor OS. Conclusions: This multicenter study confirms that prolonged survival can be achieved in selected patients suitable for PC and LM surgery if they underwent multimodality treatment including surgical treatment of PC and LM with curative intent, using intraperitoneal chemotherapy.