bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of the phase 1b study of ABBV-399 (telisotuzumab vedotin; teliso-v) in combination with erlotinib in patients with c-Met+ non-small cell lung cancer by EGFR mutation status.
Authors: Camidge D. Ross , Barlesi Fabrice , Goldman Jonathan Wade , Morgensztern Daniel , Heist Rebecca Suk , Vokes Everett E. , Spira Alexander I. , Angevin Eric , Su Wu-Chou , Hong David S. , Strickler John H. , Motwani Monica , Sun Zhaowen , Parikh Apurvasena , Noon Elysa , Wu Jun , Kelly Karen 
Published: May 2019

3011 Background: Telisotuzumab vedotin (ABBV-399; teliso-v [T]) is a c-Met–targeted antibody and MMAE drug conjugate. Activity of T was shown in late-line c-Met+ non-small cell lung cancer (NSCLC) irrespective of EGFR mutation (M+) status. We present mature data from the T+ erlotinib (E) cohort of a phase 1b study (NCT02099058) by EGFR M+ status. Methods: T was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg IV Q3W, and E at 150 mg PO QD/prior tolerated dose in adult patients (pts) with advanced NSCLC. Efficacy-evaluable pts were c-Met+ (central lab IHC H-score ≥150 or local lab MET amplification/Ex 14 skipping) and had ≥1 postbaseline scan or discontinued study. EGFR M+ was defined as del19 or L858R by local lab. PK was assessed. Results: As of Dec 2018, 42 NSCLC pts received T+E; 37 were c-MET+ (36 evaluable; 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 pts (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (Gr; ≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Gr 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Gr ≥3 (≥10%) AE: pulmonary embolism (14%). PK of T+E was similar to single-agent T. The table presents efficacy data. Conclusions: These data suggest acceptable safety and promising activity of T+E and support further study in EGFR M+ c-Met+ NSCLC pts for whom frontline EGFR TKI failed. Clinical trial information: NCT02099058. [Table: see text]
Genome-wide cell-free DNA fragmentation profiling for early cancer detection.
Authors: Leal Alessandro , Cristiano Stephen , Phallen Jillian , Fiksel Jacob , Adleff Vilmos , Bruhm Daniel C. , Jensen Sarah Østrup , Medina Jamie E. , Palsgrove Doreen N. , Niknafs Noushin , Anagnostou Valsamo , Forde Patrick M. , Brahmer Julie R. , Fijneman Remond , Johansen Julia S. , Nielsen Hans J. , Meijer Gerrit A. , Andersen Claus Lindbjerg , Scharpf Robert B. , Velculescu Victor E. 
Published: May 2019

3018 Background: Analyses of cell-free DNA (cfDNA) in the blood provide a noninvasive diagnostic avenue for patients with cancer. However, cfDNA analyses have largely focused on targeted sequencing of specific genes, and the characteristics of the origins and molecular features of cfDNA are poorly understood. We developed an ultrasensitive approach that allows simultaneous examination of a large number of abnormalities in cfDNA through genome-wide analysis of fragmentation patterns. Methods: We used a machine learning model to examined cfDNA fragmentation profiles of 236 patients with largely localized breast, colorectal, lung, ovarian, pancreatic, gastric, or bile duct cancer and 245 healthy individuals. Estimation of performance was determined by ten-fold cross validation repeated ten times. Results: cfDNA profiles of healthy individuals reflected nucleosomal patterns of white blood cells, while patients with cancer had altered fragmentation patterns. The degree of abnormality in fragmentation profiles during therapy closely matched levels of mutant allele fractions in cfDNA as determined using ultra-deep targeted sequencing. The sensitivity of detection ranged from 57% to > 99% among the seven cancer types at 98% specificity, with an overall AUC of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cfDNA analyses detected 91% of cancer patients. Conclusions: This effort is the first study to demonstrate genome-wide cell-free DNA fragmentation abnormalities in patients with cancer. Results of these analyses highlight important properties of cfDNA and provide a facile approach for screening, early detection, and monitoring of human cancer.
A phase I study of pazopanib with weekly paclitaxel and carboplatin in advanced solid tumors.
Authors: Chan Nancy , Portal Daniella E. , Moss Rebecca Anne , Silk Ann W. , Stein Mark N. , Aisner Joseph , Malhotra Jyoti , Shih Weichung , Lin Hongxia , Kane Michael P. , Mehnert Janice M. , Tan Antoinette R. 
Published: May 2019

3021 Background: Pazopanib (pazo) is an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit. It is a weak inhibitor of CYP3A4 and CYP2C8 and may decrease paclitaxel (P) clearance. Daily pazo with P and carboplatin (C) every 21 days was not feasible on a previous study. We hypothesized that pazo dosed intermittently and on a different day from P and C may be tolerable. We sought to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of pazo with weekly P and C. Methods: Using a 3+3 standard design, a schedule of P 60-80 mg/m2 and C AUC2 on days 1, 8, and 15 with pazo 400-800 mg on days 2-5, 9-12, and 16-26 on a 28-day cycle was evaluated. Pazo alone could be continued if P and C were omitted due to maximal benefit or toxicity. PK was collected during cycles 1 and 2. Results: 34 patients (pts) were treated over 6 dose levels (Table). Mean age 57 (37-79). Tumor types: breast (22), lung (3) and other (9); 27 had prior platinum. Delay in starting cycle 2 due to grade 3 neutropenia was a DLT at dose level 2 and 5. Pts on 5A missed dosing during C1 and C2 due to neutropenia and required subsequent growth factor, and this was deemed unlikely to be sustainable long-term. All grade toxicities included anemia (62%), neutropenia (59%), and thrombocytopenia (56%). Protocol-defined MTD was not determined. PK analysis showed a dose proportional increase in pazo concentration, consistent with previous reports. Pazo did not alter the PK of C. Cmax of P was higher C2D1 vs C1D1; mean Cmax ratio between C2D1:C1D1 was 1.63 (95% CI:1.29-1.96). There were 11 objective responses (3 CRs, 8 PRs). Five breast pts were on pazo alone for a median of 9 cycles (2-52) with CR (2), PR (2) and SD (1); a squamous cell of unknown primary in CR received 22 cycles. Clinical trial information: NCT01407562. Conclusions: PK confirm that pazo is a weak inhibitor of CYP3A4 and CYP2C8. Myelosuppression was a major adverse event at all dose levels. MTD was not determined. Antitumor activity was achieved with this alternate combination schedule and sustained responses from sequential pazo monotherapy was observed.[Table: see text]
A phase I dose-finding and pharmacokinetics study of CPC634 (nanoparticle entrapped docetaxel) in patients with advanced solid tumors.
Authors: Atrafi Florence , Dumez Herlinde , Mathijssen Ron H.J. , Menke Catharina Wilhelmina , Costermans Jo , Rijcken Cristianne J.F. , Hanssen Rob , Eskens Ferry , Schoffski Patrick 
Published: May 2019

3026 Background: CPC634 is a novel product with docetaxel temporarily entrapped within stabilized CriPec nanoparticles. We performed the first-in-human study with CPC634 (NCT02442531). Methods: Patients (≥18 years) received CPC634 intravenously either 3-weekly (Q3W) (part 1, 15-100 mg/m2), 2-weekly (Q2W) (part 2, 45 mg/m2) or Q3W with dexamethasone premedication (part 3) following a 3+3 design. Primary objectives were to assess safety, establish the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and to evaluate the pharmacokinetic (PK) profile of CPC634. Results: Thirty-three patients (part 1; n = 24, part 2; n = 3, part 3; n = 6) were treated. Skin toxicity was dose limiting at doses > 60 mg/m2 in part 1, and at a 45 mg/m2 dose in part 2. Skin toxicity was cumulative but resolved after ceasing treatment. The MTD in part 1 was set at 70 mg/m2. In part 3, the 60 mg/m2 was explored which resulted in improved skin tolerability even after repeated administrations without dose limiting toxicities. The RP2D was therefore set at 60 mg/m2 with dexamethasone premedication. Grade ≥3 adverse events (CTCAE version 4.03) were skin toxicity (21%), fatigue (8%), neutropenia (6%), peripheral sensory (8%) and motor neuropathy (4%), stomatitis (4%), infections (4%) and hypomagnesemia (3%). Alopecia grade 1 was reported in 15% of patients. CPC634 exhibited a dose-proportional PK profile. One partial response and sixteen cases of stable disease (RECIST 1.1) were confirmed in part 1 and in part 3 as best response. Conclusions: CPC634 could be administered safely but showed cumulative, though reversible skin toxicity at high doses. The RP2D was set at 60 mg/m2 Q3W with dexamethasone premedication. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) is currently ongoing. Clinical trial information: NCT02442531.
Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG) in patients with advanced solid tumors.
Authors: Abdel Karim Nagla Fawzy , Ahmad Imran , Gaber Ola , Eldessouki Ihab , Olowokure Olugbenga Olanrele , Farooq Maria , Morris John Charles 
Published: May 2019

3027 Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]
Associations of insulin-like growth factor binding proteins and adiponectin with disease progression and mortality in metastatic colorectal cancer: Results from CALGB/SWOG 80405 (Alliance).
Authors: Guercio Brendan John , Venook Alan P. , Zhang Sui , Ou Fang-Shu , Niedzwiecki Donna , Lenz Heinz-Josef , Innocenti Federico , Pollak Michael N. , Nixon Andrew B. , Mahoney Michelle R. , O'Neil Bert , Shaw James Edward , Polite Blase N. , Denlinger Crystal S. , Atkins James Norman , Goldberg Richard M. , Mayer Robert J. , Blanke Charles David , Fuchs Charles S. , Meyerhardt Jeffrey A. 
Published: May 2019

3035 Background: Energy balance-associated biomarkers such as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been associated with risk and prognosis of various malignancies. Their relationship to disease progression and mortality in metastatic colorectal cancer (mCRC) requires further study. Methods: In a prospective cohort study, baseline plasma IGFBP-3, IGFBP-7, C-peptide, IGF-I, and adiponectin were measured at trial registration among 1,086 patients participating in a National Cancer Institute-sponsored clinical trial of first-line therapy for mCRC. We used Cox proportional hazards regression to adjust for confounders and examine associations of biomarkers with overall (OS) and progression-free survival (PFS). Results: Higher plasma IGFBP-3 was associated with longer OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .003). Compared to patients in the lowest IGFBP-3 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 0.58 (95% CI 0.42 to 0.78) and for disease progression or mortality of 0.60 (95% CI 0.45 to 0.82). Higher plasma IGFBP-7 was associated with shorter OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .02). Compared to patients in the lowest IGFBP-7 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 1.52 (95% CI 1.24 to 1.88) and for disease progression or mortality of 1.28 (95% CI 1.05 to 1.57). C-peptide and IGF-I were not significantly associated with patient outcomes (adjusted Ptrend = .73 and .30 for OS). Adiponectin was not associated with OS; there was a U shaped association between adiponectin and PFS, wherein low and high values were associated with shorter PFS ( Pnon-linear trend = .03). Conclusions: In patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with reduced risk of disease progression and mortality. These data suggest that energy-balance associated biomarkers may offer prognostic and biologic insights into mCRC. Support: U10CA180821, U10CA180882, BMS, Genentech, Pfizer, Sanofi; https://acknowledgments.alliancefound.org .
Predictive and prognostic values of circulating tumor DNA (ctDNA) clearance in osimertinib treated advanced non-small cell lung cancer cohort.
Authors: Song Yong , Ma Shenglin , Shi Meiqi , Xu Xingxiang , Chen Xueqin , Wang Yong , Yang Zhenhua , Zhang Tengfei , Li Min , Li Haiyan , Zhang Lu , Mao Xinru 
Published: May 2019

3036 Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. CtDNA, validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC pts. Methods: This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC pts who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 pts, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes. Results: Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 pts, p = 0.004) and P53 pathways (43 pts, p = 0.032) were associated with shorter OS ( p53 was excluded from analysis due to high mutation frequency). Interestingly, pts with undetectable ctDNA at first follow-up (within 50 d, n = 41) were correlated with longer PFS (p = 0.009) and OS (p = 0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 pts experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Pts with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p = 0.035) and p53 (p = 0.023) mutations at radiological PD. In addition, pts with CNA at radiological PD had shorter PFS (p = 0.002) and OS (p = 0.052). Conclusions: This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for pts undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.
Can the enumeration of circulating tumor cells (CTCs) and the characterization of circulating tumor DNA (ctDNA) provide insight into organ tropism in metastatic breast cancer (MBC)?
Authors: Gerratana Lorenzo , Zhang Qiang , Shah Ami N. , Davis Andrew A. , Zhang Youbin , Wehbe Firas , Qiang Wenan , Flaum Lisa E. , Finkelman Brian , Gradishar William John , Platanias Leonidas C. , Behdad Amir , Cristofanilli Massimo 
Published: May 2019

3038 Background: Liquid biopsy provides real-time data about prognosis and actionable mutations in MBC. The aim of this study was to explore the combination of ctDNA analysis and CTCs enumeration in estimating target organs more susceptible to MBC involvement. Methods: This retrospective study analyzed 85 MBC patients (pts) characterized for both CTCs and ctDNA at baseline. CTCs were isolated through the CellSearch kit (Menarini Silicon Biosystems, PA), while ctDNA was analyzed using the Guardant360 NGS-based assay (Guardant Health, CA). Pts with ≥ 5 CTC/7.5 ml of blood were defined as Stage IV aggressive as previously reported (Cristofanilli et al 2019). Statistical associations were explored through uni- and multivariate logistic regression and Fisher’s exact test. Results: 37% of pts were diagnosed with hormone receptor positive (HRpos) MBC, 26% with HER2-positive MBC and 37% with triple negative MBC (TNBC), 28 pts (33%) were defined as stage IV aggressive. The most observed metastatic sites were bone (37%), lymph nodes (29%), lung (27%) and liver (25%). In multivariate analysis, IBC and ESR1 mutations were the only significant factors associated with liver metastases (respectively, OR 0.12, P = 0.038 and OR 24.01, P = 0.019), while no associations were found with respect to lung localizations. Intriguingly, all HRpos MBC pts with ESR1 mutations had bone metastases (P = 0.022), while IBC and Stage IV aggressive were independently associated with bone metastases (respectively OR 0.10, P = 0.006 and OR 19.92, P = 0.003). FGFR1 and NF1 were associated with lymph node localizations (OR 3.68, P = 0.046, OR 4.39, P = 0.031, respectively), while CDK6 and TP53 alterations were associated with serosal involvement (OR 14.34, P = 0.029, OR 0.08, P = 0.031, respectively). Notably, TNBC and IBC were both associated with soft tissue spreading (respectively OR 3.7, P = 0.011, OR 2.79, P = 0.018). Conclusions: These results suggest that ctDNA and CTCs enumeration could give useful insights on MBC organotropism, suggesting a possible role for future monitoring strategies that dynamically focus on high-risk organs defined by tumor biology.
Development and analytical validation of a 523-gene clinical assay for cell-free DNA.
Authors: Harrington Robin , Das Biswajit , Jiang Tingting , LoCoco Jennifer S. , Patidar Rajesh , Peach Amanda , Zhao Chen , Camalier Corinne , Chang Ting-Chia , Chen Alice P. , Chen Li , Forbes Thomas , Katz Sigrid , Nair Nikitha , Sims David J. , O'Sullivan Coyne Geraldine Helen , Takebe Naoko , Williams Paul M. , Karlovich Chris Alan , Doroshow James H. 
Published: May 2019

3039 Background: Liquid biopsies are emerging as a powerful complement to tumor biopsies for the clinical management of cancer patients. A large gene panel with robust analytical performance that accurately assesses variants, tumor mutational burden (TMB), and microsatellite instability in plasma would be of high value for immunotherapy studies, monitoring minimal residual disease and early cancer detection. To this end, we have completed the initial validation for the cell-free DNA (cfDNA) assay, TruSight Oncology 500 (TSO500), which interrogates the full coding region of 523 genes plus selected intronic regions for fusion detection in 23 driver genes. Methods: Cell-free DNA was extracted from plasma collected from Streck or EDTA blood tubes and quantitated to achieve an assay input of ≥10 ng. Libraries were constructed using unique molecular identifiers (UMIs) and duplex barcodes for error correction, then enriched by target capture and sequenced on a NovaSeq 6000. Healthy donor (HD) specificity assessment used matched white blood cell results to filter germline and clonal hematopoiesis variants. Contrived specimens were used to evaluate sensitivity. Single nucleotide variants (SNVs) (n = 36), insertion/deletions (indels) (n = 19), copy number variants (CNVs) (n = 6), and fusions (n = 5) were tested in 2 multi-site replicates. Results: Sensitivity of detection at 0.5% variant allele fraction (VAF) was > 95% and > 97% for SNVs and indels, respectively. All expected CNVs were identified at the targeted threshold of ≥1.3X change and showed strong correlation with matched digital PCR results. All fusions were identified at ≥0.4% VAF. Specificity in HD was > 99.99%. In 22 temporally matched tumor and blood samples from late-stage patients, 58% of all reportable mutations in tumor were identified in cfDNA. Preliminary TMB analysis identified one TMB high case with POLE p.P286R observed in both tissue and cfDNA. Conclusions: In this initial validation study the TSO500 cfDNA assay exhibited high sensitivity and specificity consistent with requirements for clinical applications. Ongoing studies will further evaluate TSO500 as a complement or potential alternative to tissue biopsy for the genomic profiling of cancer patients.