bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and tolerability of veliparib, an oral PARP inhibitor, and M6620 (VX-970), an ATR inhibitor, in combination with cisplatin in patients with refractory solid tumors.
Authors: Mittra Arjun , O'Sullivan Coyne Geraldine Helen , Do Khanh Tu , Piha-Paul Sarina Anne , Kummar Shivaani , Takebe Naoko , Bruns Ashley , Juwara Lamin , Rubinstein Lawrence , Hogu Murielle , Kinders Robert J. , Parchment Ralph E. , Miller Brandon , Wilsker Deborah , Monge B. M. Cecilia , Khan Sabrina Sharmin , Doyle L. Austin , Doroshow James H. , Chen Alice P. 
Published: May 2019

3067 Background: M6620 (M), a potent ATR inhibitor, has synergistic activity with cisplatin (C) in multiple preclinical models, resulting in DNA damage and antitumor activity. We hypothesize that inhibition of both homologous recombination and base excision repair through the combination of M6620 and veliparib (V, a potent inhibitor of PARP1/2) would result in accumulation of lethal double stranded breaks induced by cisplatin and increased antitumor activity and initiated a phase-1 dose escalation trial of this combination in patients (pts) with advanced solid tumors (NCT02723864). Methods: This is a standard 3+3 dose escalation design with 21-day cycles. M is given IV day 2 (D2) and D9; V orally twice daily D1-3 and D8-10; C IV D1 (and D8 from dose level 3 [DL3] onwards) at 40 mg/m2 (with option of holding after cycle 6). Primary objectives: safety; tolerability; maximum tolerated dose (MTD). Secondary objectives: pharmacodynamic (PD) biomarkers; antitumor activity. Dose-limiting toxicity (DLT) evaluated during cycle 1, response using RECIST 1.1. Results: Thirty-seven patients enrolled, median 5 lines of prior therapy (Range 1-12). MTD: V 200 mg, M 210 mg/m2, C 40 mg/m2 (DL6). DLT: grade (gr) 4 thrombocytopenia (DL4), hypophosphatemia (not resolved in 24 hrs., DL3), infusion reaction (DL7). Common gr 3/4 toxicities: anemia (41%), thrombocytopenia (30%), neutropenia (27%), hyponatremia (11%) and hypophosphatemia (8%). Of 34 pts evaluable for response: 2 partial response (PR) (6%, 1 confirmed & 1 transient), 22 stable disease (SD) (65%, median 4 cycles, range 2-11). Of 24 pts with PR/SD, 22 had prior platinum chemotherapy. After July 2018, V was held for gr ≥2 anemia until improved to gr 1, followed by dose reduction. Of 5 pts treated in this period, 3 required V held. PD analysis of circulating tumor cells is underway to elucidate biomarkers of DNA damage and apoptosis. Conclusions: This combination of M6620, veliparib and cisplatin is safe, with activity seen in pts having received prior platinum. The most common toxicity was anemia, which prevented adequate delivery of veliparib. While MTD was established in a heavily pretreated population, consideration should be given to continued dose escalation in pts who have received fewer prior lines of therapy. Funded in part by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT02723864.
[18F] Fluciclatide PET as a biomarker of clinical response to combination therapy of pazopanib and paclitaxel in patients with platinum-resistant or platinum-refractory advanced ovarian cancer: Results of a phase Ib study.
Authors: Sharma Rohini , Valls Pablo Oriol , Inglese Marianna , Dubash Suraiya Rahim , Chen Michelle , Gabra Hani , Montes Ana , Challapalli Amarnath , Tharakan George , Chambers Edward , Cole Tom , Lozano-kuehne Jingky , Barwick Tara , Aboagye Eric 
Published: May 2019

3070 Background: Angiogenesis has been shown to be a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both up-regulated in tumour-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. Methods: We conducted an open-label, phase Ib study in patients with platinum resistant/refractory ovarian cancer. Patients received 1 week of single agent pazopanib (800mg daily) followed by combination therapy with weekly paclitaxel 80mg/m2. Following completion of 18 weeks of therapy, patients continued with single agent pazopanib until disease progression. Dynamic [18F]Fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. Results: Fourteen patients were included in the intention-to-treat analysis. Complete and partial response was seen in 7 patients (54%). Median progression free survival (PFS) was 7.97 months, and overall survival (OS) was 18.5 months. A reduction in [18F]fluciclatide uptake was observed following 1 week of pazopanib, and the reduction in uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and FGF were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modelling indicated a reduction in K1 and Ki following pazopanib indicating reduced radiotracer delivery and retention. Conclusions: Combination therapy followed by maintenance pazopanib is effective and tolerable in patients with platinum resistant/refractory ovarian cancer. We have shown that [18F]fluciclatide-PET uptake parameters alter with pazopanib therapy indicating an anti-angiogenic response. Clinical trial information: NCT01608009.
Clinical impact of tissue of origin testing and mutation profiling in the Solving Unknown Primary Cancer (SUPER) national prospective study: Experience of the first two years.
Authors: Mileshkin Linda R. , Sivakumaran Tharani , Etemadmoghadam Dariush , Tothill Richard , Fellowes Andrew , Fox Stephen B. , Guccione Lisa , Freimund Alison E. , deFazio Anna , Wilcken Nicholas , Gao Bo , Singh Madhu Sudan , Collins Ian M. , Richardson Gary Edward , Steer Christopher B. , Warren Mark Andrew , Karapetis Christos Stelios , Bryant Cindy , Schofield Penelope , Bowtell David 
Published: May 2019

3072 Background: Cancer of unknown primary (CUP) has a poor prognosis with a median survival of less than 12 months. SUPER is a prospective cohort study designed to create a national biobank of patients (pts) with no confirmed primary site following diagnostic work-up. Tumor and blood samples undergo mutational profiling for actionable mutations using the 386 gene PeterMac Comprehensive Cancer Panel (CCP) plus CUPGuide, a microarray gene-expression site-of-origin assay. We aimed to determine the clinical impact of CUPGuide and CCP profiling. Methods: 172 pts were enrolled between 2013-2015. Baseline demographics, treatments, investigations and clinico-pathological characteristics were collected over 12 months. Clinicians completed clinical management questionnaires before and after receiving results. Results: Molecular analysis was performed for 124/172 (72.1%) pts with sufficient DNA and/or RNA. CUPGuide was completed for 97/124 (78.2%); primary site predictions were made in 84/97 patients (86.6%). The most common primary site predictions were lung, gastric, ovary and breast. CUPGuide predictions resulted in a change in management in 10/84 (12%) of cases and confirmed current management already commenced by the clinician in 53/84 (63%). Mutation profiling was completed in 103/124 (83.1%) pts with actionable mutations found in 11 pts, 4 of whom received subsequent targeted therapy. Testing was considered to have a clinical impact in 70/120 cases (58%): either resulting in a change in treatment (n = 14), diagnosis of a pathogenic germline finding (n = 8) or a moderate/high confidence tissue of origin prediction (n = 58). There were two deaths prior to the availability of the CUPGuide results and eleven deaths prior to availability of the CCP results. Conclusions: Molecular analysis for CUP pts has clinical impact in the majority of cases. Timeliness of return of results, drug access and insufficient tissue for testing are barriers to greater impact that need to be addressed to improve the care of pts affected by CUP.
A phase I, open label, multicenter dose escalation study of AZD2811 nanoparticle in patients with advanced solid tumors.
Authors: Johnson Melissa Lynne , Cosaert Jan G. C. E. , Falchook Gerald Steven , Jones Suzanne Fields , Strickland Donald , Greenlees Carol , Charlton Julie , MacDonald Alexander , Overend Philip , Adelman Carrie , Burris Howard A. , Pease Elizabeth J. , Patel Gargi Surendra , Wang Judy Sing-Zan 
Published: May 2019

3098 Background: Aurora kinase B (AURKB) represents a potential target for therapy in solid and hematological malignancies. AURKB inhibitor AZD1152 (barasertib) was previously investigated in solid tumor pts in a phase I setting. AZD2811-nanoparticle (np) is a novel, encapsulated slow release AURKB inhibitor offering several advantages over AZD1152 (Ashton S et al., Sci Transl Med 2016). We report the completed dose-escalation safety, pharmacokinetics (PK), preliminary activity and defined maximum tolerated dose (MTD) of AZD2811-np in pts with advanced solid tumors (NCT02579226). Methods: Adult pts with advanced solid tumors received AZD2811-np IV on Day 1 (D1) and 4 (D4) Q4 week (wk) in six cohorts 15-200 mg/infusion without the use of g-csf in cycle 1. D1 Q4wk and Q3wk schedules were investigated up to 600 mg/infusion (including cohorts with mandatory g-csf prophylaxis on day 8). A standard 3+3 design was used. PK was assessed in cycle 1. Results: 50 pts were recruited into 12 cohorts. D1, D4 Q4wk schedule: 24 pts (15, 25,38, 50, 100 mg/infusion (n=3/cohort), 200 mg/infusion (n=9)). All cohorts were tolerated. Transient grade 4 neutropenia was observed in 7/9 pts at 200 mg/infusion, including 1 DLT (gr4 > 7 days) D1 Q4wk: 200 mg(n=3) was tolerated. D1 Q3wk: 23 pts were evaluated (200/400 mg (n=3,7), and 400/600/500 mg with mandatory g-csf (n=3/5/6)). 400 mg without g-csf was not tolerated (1 gr3 mucosal inflammation & 1 gr4 neutropenia > 7 days). 600 mg with g-csf was not tolerated (gr3 febrile neutropenia & gr3 fatigue). 25/50 pts experienced AE ≥gr 3 (21 considered AZD2811-np-related, 19 neutropenia-related, no deaths within-DLT period). AZD2811-np caused transient gr1/2 fatigue, nausea, diarrhoea and mucosal inflammation. AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours irrespective of schedule. Released AZD2811 concentrations ~1% of total. 14 pts (28%) had disease stabilisation. 1 prostate ca. pt had a confirmed partial response (PR) (continued tx to 451 days). Conclusions: The MTD for AZD2811-np is 500 mg D1 Q3wk. AZD2811-np is now being investigated in a small cell lung cancer expansion. Clinical trial information: NCT02579226.
The landscape of RET alterations from 56,970 adult patients with cancer: Clinical implications.
Authors: Andreev-Drakhlin Alexander , Roszik Jason , Subbiah Vivek 
Published: May 2019

3106 Background: Activating receptor-tyrosine kinase rearranged during transfection ( RET) mutations and fusions have been recognized as potent drivers of oncogenesis. Recent identification of highly potent and selective RET inhibitors holds great promise in the management of RET-dependent tumors. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Methods: We analyzed 59,347 samples from 56,970 patients available from AACR Project GENIE (Cancer Discov. 2017) database for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types. Results: A total of 1414 RET alterations were detected, including 91 fusions (6.4%), 1166 missense mutations (82.5%), 136 truncating mutations (9.6%), and 21 in-frame mutations (1.5%). RET fusions were observed in 0.15% of tumor samples and were most commonly identified in non-small cell lung cancer, thyroid cancer, colorectal cancer, prostate cancer, and gastric cancer (62.6%, 18.6%, 5.5%, 4.4%, 3.3% of identified RET fusions, respectively). RET fusions were significantly co-altered with MAPK3/ERK1 (p=0.045), SETD2 (p=1.36E-07 ), and EIF4E (p=0.045), while there was a negative association between RET fusions and EGFR (p=0.009634) , TP53 (p=0.02267), and KRAS (p=2.53E-05) alterations. Most common RET gene upstream partners were KIF5B, CCDC6, and NCOA4 (42.9%, 24.2%, 7.7% of identified RET fusions, respectively). RET missense mutations were found in 2.0% of tumor samples; 136 (11.7%) of identified missense mutations, including 8 RET gatekeeper V804M/L mutations, were characterized as likely oncogenic, 12 (1.0%) as likely benign, and 1018 (87.3%) as variants of unknown significance using OncoKB database. RET amplifications occurred in 1.5% of tested samples. Conclusions: While RET fusions represent extremely rare events in multiple cancers, RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted. MAPK pathway co-alterations in patents with RET fusions may present a strategy for future therapeutic combinations.
Cell-specific upregulation of lung “cancer signature genes” in the small airway epithelium of asymptomatic smokers.
Authors: Rostami Mahboubeh , Zuo Wu-Lin , Crystal Ronald G. , Mezey Jason G. 
Published: May 2019

3109 Background: Most lung cancers are derived from the small airway (6th -23rd generations) epithelium (SAE). While a pathogenic mutation in a driver gene is critical to transform a SAE cell to a malignant cell, single cell analysis of lung cancers has demonstrated that individual cancer cells have transcriptional alterations in many “cancer signature genes” (Lambrechts D et al, Nature Med 2018; 24:1277) that are not driver genes, but likely support the malignant state. Based on the concept that dysregulation of many of these genes facilitate the malignant state, we hypothesized that, with the stress of smoking, some of these cancer-supporting transcriptional modifications occur long before the random hit with a driver mutation, providing a soil for the driver mutation. Methods: To assess this hypothesis, we applied drop-seq single cell transcriptome analysis to assess SAE recovered by fiberoptic bronchoscopy and brushing of n = 3 healthy non-smokers and n = 3 healthy smokers. Using unsupervised clustering, 11 cell types were identified including major SAE cell types (basal, intermediate, club, mucous and ciliated), rare epithelial cells (ionocyte, neuroendocrine and undefined NCLhi) and rare immune/inflammatory cell (Tcell, mast, antigen presenting). Results: Comparison of smokers and nonsmokers showed that smoking significantly altered the transcriptome (n = 426 genes upregulated, n = 572 genes downregulated) in different SAE cell types; 21% -56% of smoking-upregulated genes in the major SAE cell population are identified as “cancer signature genes”, where a number have cell-specific smoking regulated patterns within individual cell types including HSPB1 in mucous cells, ADH7 in ciliated, LAMB3 in basal and intermediate cells, MIF intermediate and club cells, ALDH3A1 in all main SAE cell types. Conclusions: These data support the concept that cigarette smoking, long before the development of cancer, reprograms specific SAE cells to provide the biological soil to support driver genes to function.
Integrative analyses of signaling and DNA damage repair pathways in patient-derived xenograft (PDX) models from NCI’s patient-derived models repository (PDMR).
Authors: Das Biswajit , Evrard Yvonne A. , Chen Li , Patidar Rajesh , Vilimas Tomas , McCutcheon Justine N. , Peach Amanda , Nair Nikitha , Jiwani Shahanawaz , Borgel Susanne , Carter John , Divelbiss Raymond , Radzyminski Marianne , Stottlemyer Jesse , Ju Zhenlin , Akbani Rehan , Karlovich Chris Alan , Williams Paul M. , Hollingshead Melinda G. , Doroshow James H. 
Published: May 2019

3111 Background: Patient-derived xenografts (PDXs) are increasingly being used in translational cancer research for preclinical drug efficacy studies. The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (NCI PDMR; pdmr.cancer.gov ) of PDXs with clinical annotation, proteomics, and comprehensive genomic datasets to facilitate these studies. Here, we present an integrative genomic, transcriptomic, and proteomic analysis of critical signaling and DNA damage repair pathways in these PDX models, which represent 9 common and multiple rare tumor histologies. Methods: 304 PDX models from 294 patients were established from various solid tumor histologies from patients with primary or metastatic cancer. Whole Exome Sequencing, RNA-Seq and Reverse Phase Protein Array (RPPA) were performed on 2-9 PDXs per model across multiple passages. An integrative workflow was applied on multiple data sets to detect pathway activation. Results: We profiled 10 signaling and 5 DNA repair pathways in the PDMR dataset. We observed that: (i) a large fraction (40%) of PDX models have at least 1 targetable mutation in the RTK/RAS and/or PIK3CA pathways; (ii) 131 models (45%) have putative driver and oncogenic mutations and copy number variants (CNVs) in the WNT, TGFRb , NRF2 and NOTCH pathways. In addition, 17% of PDX models have targetable mutations in DNA damage repair pathways and 20 PDMR models have a DNA mismatch repair defect (MSI-H). We confirmed activation of the signaling pathways in a subset of PDX models by pathway enrichment analysis on gene expression data from RNASeq and phosphoprotein-specific antibody binding data from RPPA. Activation of DNA repair processes was confirmed by enrichment of relevant mutational signatures and loss of heterozygosity in these PDX models. Conclusions: Genomic analysis of NCI PDMR models revealed that a large fraction have clinically relevant somatic alterations in key signaling and DNA damage repair pathways. Further integrative analyses with matched transcriptomic and proteomic profiles confirmed pathway activation in a subset of these models, which may prioritize them for preclinical drug studies.
A randomized, multicenter clinical trial to determine the efficacy and safety of pegfilgrastim (GEMA BIOTECH) compared to pegfilgrastim (Roche) for prevention of chemotherapy induced neutropenia in patients with breast cancer.
Authors: Richardet Martin Eduardo , Kowalyszyn Ruben Dario , Varela Mirta Susana , Ortiz Eduardo , Micheri Cristian , Zarba Juan Jose , Kahl Susana , Klimovsky Ezequiel , Federico Andrea Alicia , Fein Luis Enrique , Cassini Jorge Horacio , Cortese Gustavo , Visintini Jaime Florencia , Cordeiro Lucas , Lago Nestor Ruben 
Published: May 2019

3113 Background: Peg-Neutropine, GEMA BIOTECH SAU biosimilar Peg-Filgrastim, is the first Peg-Filgrastim approved in LATAM for prevention of febrile neutropenia in patients treated with myelosuppressive chemotherapy. Methods: Study population: women with stage 2, 3 or 4 of breast cancer scheduled to receive 4 or 6 cycles of chemotherapy (with Taxane) at 3 weeks interval. Stratification was based on breast cancer stage. Study drug was administered subcutaneously in a 6 mg dose. The study was blind to the assessors. The primary endpoint was Duration of Severe Neutropenia (DSN, Absolute Neutrophil Count-ANC < 500/mm3) in the first cycle of chemotherapy. Secondary endpoints were incidence of severe neutropenia (SN), other efficacy measures, and incidence of ADRs. The non-inferiority margin for DSN was estimated in less than 1 day. Results: A total of 120 subjects were randomized 1:1, 58 were treated with Peg-Neutropine and 62 with Peg-Filgrastim (Roche). Efficacy: SN was developed in 52/283 (18,4%) cycles with Peg-Neutropine in 27 patients and 48/297 (16,2%) cycles with Peg-Filgrastim (Roche) in 20 patients (p=0,4836). In the first cycle, 16 patients with Peg-Neutropine and 11 patients with Peg-Filgrastim (Roche) developed SN. In per protocol analysis mean DNS in the first cycle was 0,78 ± 1,53 days for Peg-Neutropine group and 0,53±1,25 for Peg-Filgrastim (Roche) group (95% IC for the difference -0,26; 0,76). Per ITT analysis the mean DSN was 0,90±1,79 for Peg- Neutropine group and 0,50±1,21 for Peg-Filgrastim (Roche) group , (95% IC for the difference -0,15; 0,95). For all the efficacy secondary endpoints the differences were not statistically significant. Safety: 7 ADRs were developed by 3 subjects with Peg-Neutropine and 31 ADRs were developed by 10 subjects with Peg-Filgrastim (Roche). The most common reaction was myalgia, and other ADRs were arthralgia, asthenia, bone pain and acid sensitive syndrome. Conclusions: Based on the non-inferiority margin established we conclude that Peg-Neutropine is biosimilar to Peg-Filgrastim (Roche). Clinical trial information: NCT03404752.
Correlation between NDRG1 gene polymorphism and neuropathy (N) in metastatic breast cancer (MBC) patients (pts) enrolled in the PAINTER study (Polymorphism And INcidence of Toxicity in ERibulin treatment).
Authors: La Verde Nicla Maria , Damia Giovanna , Garrone Ornella , D'Onofrio Loretta , Fabi Alessandra , Ciccarese Mariangela , Generali Daniele Giulio , Nunzi Martina , Poletto Elena , Pedrazzoli Paolo , Cretella Elisabetta , Scandurra Giuseppa , Meattini Icro , Bertolini Alessandro Stefano , Cavanna Luigi , Romagnoli Emanuela , Legramandi Lorenzo , Guffanti Federica , Bocci Barbara , Farina Gabriella 
Published: May 2019

3116 Background: MBC is an incurable disease and therefore treatment focuses mainly on prolonging pts survival and improving quality of life. Eribulin (E) is a microtubule inhibitor that increased overall survival in pretreated pts. E peripheral N is reported in 13.9-35% of cases. PAINTER main objective was to survey tolerability of E in real life in MBC, while secondary endpoints were to investigate the relationships between specific genetic polymorphisms and incidence and severity of peripheral N. Methods: This is a multicenter, interventional, single-arm, phase IV study, that enrolled pts who received E after taxanes and antracyclines (dose 1.4 mg/m2 day 1, 8 every 21 days). PAINTER study follow-up is still ongoing. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit. Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with avaliable clinical data and who completed E treatment. N was evaluated by medical examination. The associations between peripheral N (any grade) and the selected polymorphisms were evaluated with Fisher exact test. Results: From May 2014 to June 2018, 180 pts were enrolled in the PAINTER study from 20 Italian hospitals and 135 were analysed for the present report. Pts and tumor characteristics were as follow: median age 62 years (31-85), ductal carcinoma 78.5%, visceral disease 70.4%, luminal type 62.6%, Her2 positive 20.3%, triple negative 17.1%, previous median treatment lines for MBC 5 (0-18), previous N reported in 17.8% of pts (sensory 87.5%, motor 12.5%). N (all grades) were reported in 33.4% of patients (G3-G4: 3%). Among the selected SNPs, one allelic variant (rs2233335 G/G versus G/T or T/T) in NDRG1 gene had a statistically significant association with N (p 0.0010). Conclusions: The data reported demonstrate for the first time that the allelic variant rs2233335 (G/T and T/T) in NDRG1 gene correlates with E induced N. These data, if corroborated, will allow a tailored treatment with E. Clinical trial information: NCT02864030. [Table: see text]