julilili42/papers huggingface dataset:
Phase I/II clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 in patients with unresactable, chemotherapy-resistant peritoneal carcinomatosis.
2013-05-20

3098 Background: For therapy-resistant peritoneal carcinomatosis (PC) viruses exhibiting oncolytic properties open up new perspectives. Our phase I/II study in patients with refractory PC (NCT01443260) is designed to assess the safety, MTD, and anti-tumor activity of GL-ONC1, a recombinant vaccinia virus (VACV) genetically engineered to selectively replicate in and destroy cancer cells. Methods: GL-ONC1 was administered intraperitoneally up to 4 times every 28 days under a standard 3+3 dose escalation design. Safety was assessed using CTCAEv4.0. Anti-tumor activity was determined by “fluid biopsies” obtained via repetitive paracenteses and by serial PET-CT scans. Patient samples were collected for pharmacokinetics, pharmacodynamics and viral shedding analysis. Results: Up to now, 4 patients have received 10 doses of GL-ONC1 ranging from 10 7 to 10 8 infectious viral particles per application.Adverse events have generally been limited to grade 1/2, being mostly transient flu-like symptoms as well as increased abdominal pain resulting from treatment-induced peritonitis. No DLT was reported. No viral shedding was observed. In one gastric cancer patient, effective intraperitoneal replication of GL-ONC1 was demonstrated for more than 3 weeks. Using either anti-EpCAM or anti-VACV specific antibodies, around 5% of all ascitic cells were found to be EpCAM-positive 3 days after treatment in this patient, and only around 5-10% of these cancer cells were VACV positive at the same time point. In contrast, 4 days later (i.e. 7 days after virotherapeutic treatment), less than 2% of all ascitic cells were still EpCAM-positive, and more than 90% of these cancer cells were VACV positive. Of note, VACV-positive cancer cells morphologically showed significant degenerative changes. Conclusions: Preliminary data demonstrate that GL-ONC1 is well tolerated when infused intraperitoneally. Importantly, a single intraperitoneal delivery of GL-ONC1 was found to be sufficient to cause a dramatic decline in the number of malignant cells in the ascitic fluid, suggesting that GL-ONC1 effectively removes tumor cells in the ascites of patients with PC. Clinical trial information: NCT01443260.
Resminostat in advanced hepatocellular carcinoma (HCC): Overall survival subgroup analysis of prognostic factors in the SHELTER trial.
2013-05-20

e15088 Background: Previously published results of the phase I/II SHELTER study demonstrated efficacy and safety of the novel pan-HDAC inhibitor resminostat in second-line treatment of HCC patients (pts) who had progressed under first-line sorafenib. As patient baseline characteristics might influence treatment outcome, an analysis of their potential influence on overall survival (OS) was performed. Methods: 45 pts with advanced-stage HCC and centrally confirmed radiologic progression under first-line sorafenib were included in a multi-center, two-arm trial. Resminostat was administered either alone or in combination with sorafenib. A Cox proportional-hazards model was used to evaluate the interaction between baseline characteristics and the effect of the two treatment groups on overall survival. Results: In the combination group, pts with Child-Pugh-A, ECOG 0 or absence of vascular invasion had a statistically significant lower risk of death compared to pts with Child-Pugh-B (HR 0.19, 95% CI 0.06-0.55), ECOG 1 (HR 0.15, 95% CI 0.05-0.44), or vascular invasion (HR 0.37, 95% CI 0.15-0.93), respectively. For pts with BCLC-B there was a strong trend, although not statistically significant, of a lower risk of death when compared to pts with BCLC-C (HR 0.43, 95% CI 0.13-1.49). Etiology, prior TACE therapy, extrahepatic spread and interval between first- and second-line treatment had no impact on overall survival in this study. Similar findings were observed in the monotherapy group. Comparing the impact of these baseline characteristics in the combination and monotherapy group, no statistically significant different influence on OS between both treatment groups was observed. Conclusions: Resminostat in combination with sorafenib provides a substantial OS benefit (median OS of 8.1 months) for advanced HCC patients who had developed progressive tumor disease under first-line sorafenib therapy. Subgroup analysis of patient baseline characteristics revealed a significant influence of Child-Pugh index, ECOG classification, and vascular invasion on overall survival, whereas e.g. the interval between first- and second-line treatment had no impact on overall survival. Clinical trial information: NCT00943449.
Prognostic value of HER2 on breast cancer survival.
2013-05-20

640 Background: HER2 overexpression and overamplification have originally been described as a prognostic factor indicating a poor prognosis. However the highly effective anti-HER2 treatment was approved in 2006 after several large randomized trials showing that the prognosis in HER2 positive women could be improved. Few data has been generated comparing HER2 positive patients treated with trastuzumab with comparable HER2 negative patients. Aim of this analysis was to investigate the prognostic relevance of HER2 status in a post trastuzumab approval study. Methods: The SUCCESS trial is an open-label, multicenter, randomized controlled, phase III study comparing FEC-docetaxel (Doc) vs. FEC-Doc-gemcitabine (Doc-G) regime and 2 vs. 5 year treatment with zoledronat in 3754 patients with primary breast cancer (N+ or high risk). All patients were treated per protocol with trastuzumab, if HER2 status was shown to be positive by local pathology. Furthermore HER2 status was a stratification factor. The prognostic value of HER2 status with respect to overall survival (OS) and progression-free survival (PFS), disregarding the above stated treatment arms, was studied with Cox proportional hazards regression models in univariate as well as multivariate analyses adjusted for age, BMI, tumor size, nodal status, grading, estrogen receptor status and progesterone receptor status. Results: 2628 patients were included into this analysis. Median Follow up time was 4.8 years, 221 deaths and 412 recurrences were recorded until data base closure. HER2 was not a prognostic factor in the univariate analysis (OS: HR= 0.86, 95% CI: 0.63 to 1.19; PFS: HR = 0.95, 95% CI: 0.76 to 1.19). In the multivariate analysis all of the above stated prognostic factors were of prognostic relevance. HER2 was of prognostic relevance with a HR of 0.67 (OS, 95% CI: 0.48 to 0.92) and 0.79 (PFS, 95% CI: 0.62 to 0.99) indicating that patients with a positive HER2 status had a better prognosis. Conclusions: Patients treated with trastuzumab showed a more favourable prognosis compared to HER2 negative patients in this prospectively randomized trial, possibly due to the therapeutic effect of HER2-targeted treatment.
A phase III, randomized, double-blind study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus dacarbazine in patients (pts) with previously untreated, unresectable, or metastatic melanoma (MEL).
2013-05-20

TPS9106 Background: The 5-year survival rate for late-stage MEL is currently only 15%. Despite recent advances with ipilimumab and vemurafenib, a considerable unmet need remains for pts with previously untreated, unresectable or metastatic BRAF wild-type MEL. Objective response rate (ORR) with first-line dacarbazine, a widely used chemotherapy in MEL, is 13%, with median overall survival (OS) ranging from 5.6 to 11 months. Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation through interaction with its ligand, PD-L1. This ligand is overexpressed by multiple tumor types, including advanced MEL. The PD-1 receptor blocking antibody nivolumab demonstrated clinical activity at 0.1-10 mg/kg in a phase I study in pts with advanced MEL (n = 106), with OR in 33 pts and stable disease ≥24 weeks in 6 pts. We describe a double-blind, randomized phase III study designed to compare the clinical benefit of nivolumab vs dacarbazine in pts with advanced MEL. Methods: Approximately 410 pts with untreated, unresectable stage III or stage IV MEL will be randomized 1:1 to receive either nivolumab 3 mg/kg IV every two weeks or dacarbazine 1000 mg/m 2 IV every three weeks until disease progression or unacceptable toxicity. All pts must be BRAF wild-type as per V600 mutational testing. Pts will be stratified by PD-L1 status (positive vs negative/indeterminate) and metastatic (M) stage (M0/M1a/M1b vs M1c). PD-L1 positivity will be defined as ≥5% total membrane staining in tumor cells. Tumor response (per RECIST 1.1) will be assessed 9 weeks following randomization and every 6 weeks thereafter for the first year. After the first year, response will be assessed every 12 weeks until disease progression or treatment discontinuation. Treatment may continue beyond initial progression at the investigator’s discretion for pts showing clinical benefit and tolerating therapy. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, whether PD-L1 expression is a predictive biomarker for OS, and health-related quality of life. Clinical trial information: NCT01721772.
The PI3K inhibitor BKM120 has potent antitumor activity in melanoma brain metastases in vitro and in vivo.
2013-05-20

e20050 Background: In melanoma, the RAF-MEK-ERK and PI3K-AKT signaling pathways play a major role in melanoma progression and drug resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, vemurafenib appears to be less effective in melanoma brain metastases, and brain metastases are the most common cause of death in patients with metastatic melanoma. In our previous study we reported that the AKT survival pathway is hyperactivated in melanoma brain metastases. Methods: The current study aims to investigate the mechanisms of AKT hyperactivation and the antitumor activity of the PI3K inhibitor BKM120 in melanoma brain metastases in vitro and in vivo. Results: To simulate the tumor environment of brain metastases and extracerebral metastases, brain and matched extracerebral metastatic melanoma cells were stimulated by astrocyte- and fibroblast-conditioned medium, respectively. Both brain and extracerebral metastatic melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness in a transwell matrigel invasion assay than cells stimulated by fibroblast-conditioned medium. The PI3K inhibitor BKM120 inhibited the phosphorylation of AKT and the growth of &gt;10 newly isolated cell lines derived from melanoma brain metastases achieving growth inhibition rates of up to 80%. These effects did not depend on BRAF, NRAS or KIT mutation status. Furthermore, BKM120 potently induced apoptosis in brain metastatic melanoma cells and significantly inhibited the tumor growth of human brain metastatic melanoma cells in the brain of nude mice as shown by MRI scans. Conclusions: Brain-derived factors induce hyperactivation of the AKT survival pathway and promote invasiveness and drug resistance of melanoma cells in the brain. The PI3K inhibitor BKM120 inhibits activation of the AKT survival pathway and demonstrates potent antitumor activity in melanoma brain metastases in vitro and in vivo.
Quality of life (QOL) improvements for pomalidomide plus low-dose dexamethasone (POM + LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients (pts) enrolled in MM-003.
2013-05-20

8583 Background: Poor prognosis and therapy exhaustion have been associated with reduced QOL in RRMM. In MM-003, a randomized, multicenter, open-label phase 3 trial, POM + LoDEX (n = 302) significantly improved progression-free and overall survival vs. high-dose dexamethasone (HiDEX; n = 153) in pts who failed lenalidomide (LEN) and bortezomib (BORT) and progressed on their last therapy. This analysis evaluated QOL changes in these pts. Methods: To assess pt-reported outcomes, cross-sectional and longitudinal analyses were performed. Minimal important differences for 5 clinically relevant EORTC QLQ-C30 domains (Global Health Status, Physical Functioning, Fatigue, Emotional Functioning, and Pain) were calculated as meaningful change thresholds (1 standard error of measurement) from baseline through cycle (C) 5. Time to QOL worsening was compared between arms using the Kaplan-Meier method. Results: Favorable trends were observed for POM + LoDEX vs. HiDEX in each of the 5 relevant domains. The cross-sectional analysis indicated statistically or marginally significant (P &lt; .10) differences favoring POM + LoDEX in Global Health Status (C2, 4), Physical Function (C2, 3, 4), Emotional Function (C2, 3, 4), and Fatigue (C2) scores. Longitudinal comparisons between arms confirmed the significance of score changes for Global Health Status (C2; P = .01), Physical Functioning (C3 and 4; P = .018 and .028, respectively), Emotional Functioning (C3; P = .018), and Fatigue (C5; P = .008) for POM + LoDEX vs. HiDEX. HiDEX pts exhibited clinically meaningful worsening in Global Health Status and Physical Functioning scores vs. POM + LoDEX by C2 (P = .04) and C3 (P = .02), respectively. POM + LoDEX extended median time to meaningful worsening vs. HiDEX for Global Health Status (114 vs. 85 days, P = .05), Physical Functioning (174 vs. 106 days; P = .09), Fatigue (113 vs. 60 days; P = .02), Emotional Functioning (190 vs. 124 days; P = .04), and Pain (147 vs. 113 days; P = .2). Conclusions: In heavily pretreated pts who failed LEN and BORT, POM + LoDEX resulted in better clinical outcomes as well as improvement in clinically relevant QOL measurements over the course of treatment. Clinical trial information: NCT01311687.
4EVER: Assessment of circulating tumor cells with a novel, filtration-based method, in a phase IIIb multicenter study for postmenopausal, HER2- negative, estrogen receptor-positive, advanced breast cancer patients.
2013-05-20

591 Background: The presence of circulating tumor cells (CTCs) has been shown to be of prognostic relevance for patients with early and advanced breast cancer (BC). The usefulness of CTC assessments depends on accurate cell counts and corresponding analysis of molecular targets. The aim of this sub study was to assess the feasibility of a novel, integrated CTC platform for automated cellular protein and nucleic acid analysis in a prospective multi-center study. Methods: The German 4EVER study included patients with postmenopausal, metastastic, ER positive, HER2 negative BC, who progressed after therapy with a non-steroidal aromatase inhibitor and were treated with exemestane and the mTOR inhibitor everolimus. Baseline blood samples (TransFix vaccum tubes, Cytomark, Caltag Medsystems Ltd.) were used for CTC analysis and processed on the modified Versant kPCR Sample Prep system using 8μm pore size Whatman Nuclepore track-etched membranes (GE Healthcare Piscataway, NJ). After CTC capture, immunostaining was performed for Cytokeratin 8/18/19 and CD45. CTCs were detected by image analytics after fluorescence scanning microscopy using a dedicated software solution implemented by Siemens. The data is summarized and correlated with baseline clinical characteristics. Results: CTC counts and clinical data were available for 111 blood samples (91.7%). CTCs were found in 75 patients (67,6%), 13 patients having 1 CTC, 38 having 2-9 CTCs and 24 patients having 10 or more CTCs. In an exploratory analysis the presence of CTCs was correlated with baseline patient and tumor characteristics. There were no associations with primary TNM stage, hormone receptor status or tumor type. Conclusions: CTC assessment with this novel filtration based method was feasible in a multi-center study setting. The CTC positivity rate was within the expected range. The follow-up of this study will give first insights, how the CTC measures of this platform can be used as a prognostic tool. As this CTC assessment platform was developed to perform additional automated cellular protein and nucleic acid analysis, the usefulness might derive from these analytic tools as well. Clinical trial information: NCT01626222.
The prognostic and predictive impact of genomic grade index (GGI) versus central grade or molecular class in intermediate-risk breast cancer (BC): Results from the EC-Doc trial.
2013-05-20

1092 Background: Potential markers for adjuvant taxane-based chemotherapy (CTx) in early, intermediate-risk BC include histologic grade (HG), Ki-67, Genomic Grade (GG) or molecular classification. The randomized EC-Doc trial demonstrated improvements in DFS and OS for EC-Doc vs. FEC in patients with 1-3 positive LN. Methods: Centrally assessed protein expression data by IHC, histology/HG (n=772) and GG (n=476) were obtained. Luminal A/B classes were defined as: ER/PR+/KI-67&lt;20/&gt;20% and/or HER2+. Correlations/concordance of these factors were estimated; impact on DFS and value for predicting taxane-based CTx benefit was assessed. Results: Low, equivocal and high GG (GG-1/-EQ/-3) categories were observed among 54 (11%); 60 (13%); 358 patients (76%) and associated with decreasing 5-yr-DFS rates of 100%, 92% and 82% (p &lt; 0.001).There is only 60% concordance between local (L)/central(C) HG assessments and 63% between GG and C-HG. 37.7% of GG-3 tumors were L- HG3 vs. 72% C-HG3; 79% of C-HG2 and 83% of L-HG2 tumors were re-classified (56-71% to GGI3). Only 5.6-6% of GG1 were HG1 by L/C-HG respectively.GG was prognostic only in L-HG subgroups.In univariate subgroup analyses, EC-Doc was significantly superior to FEC: C-G3 (HR=0.58, 0.39-0.93), high Ki-67 (HR=0.55, 0.32E0.92) and GG-3 (HR=0.58, 0.34-0.99) subgroups. In multivariate analyses of HR+ disease (including age, therapy, GGI category, tumor size, LN status, central/local HG, Ki-67, HER2), either C-HG3 / high Ki-67 (as dichotomous variables) or C-HG3 / GGI (as continuous variable) were identified as independent prognostic factors.In interaction analysis, only C-HG, luminal A subtype and interaction of luminal-B/therapy were significant. If local HG was included instead of C-HG, only GG was as independent prognostic factor. Conclusions: These data support GGI as independent prognostic factor in early HR+ BC and as predictive marker regarding taxane benefit by univariate analysis. There is heterogeneity between L/C-HG and GGI. C-HG and Ki-67 assessment appear similarly informative. A predictive effect regarding benefit of taxane-containing CTx was seen in the IHC-luminal B subtype.
Evaluation of invasion patterns and their correlation with integrin alphavbeta expression in brain metastases of solid cancers.
2013-05-20

2059 Background: Understanding the pathobiology of brain metastases (BM) could guide the establishment of new targeted therapies. Methods: We collected 57 autopsy specimens of BM (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 1 kidney cancer, 2 colorectal cancer, 13 other) and histologically evaluated the patterns of invasion into the surrounding brain parenchyma. Expression of the following integrins was evaluated using immunohistochemistry: with novel antibodies for αv subunit, αvβ3, αvβ5, αvβ6 and αvβ8 integrin. Results: We observed three main invasion patterns: well-demarcated (29/57, 51%), vascular co-option (10/57, 18%) and diffuse infiltration (18/57, 32%). There was no association of invasion pattern with primary tumor type, although vascular co-option was most common in melanomas (4/10, 40%). αv subunit expression was lowest in the vascular co-option group (p = 0.05, t-test). αvβ6 levels were higher in the well-demarcated group than in the vascular co-option group (p = 0.025; t-test) and were higher in lung cancer BM than in melanoma BM (0.01, t-test). αvβ3 and αvβ5 were frequently expressed in tumoral (αvβ3: 30/57, 53%; αvβ5: 55/57, 97%) and peritumoral (αvβ3: 29/57, 51%, αvβ5: 54/57 (95%) vascular structures and 27/57 (47%) specimens showed avb5 and 6/57 (11%) αvβ3 expression on tumor cells. Prior radio- or chemotherapy did not correlate with invasion pattern or integrin expression. Conclusions: We delineate three distinct invasion patterns of BM into the brain parenchyma: well-demarcated growth, vascular co-option and diffuse infiltration. Integrin expression is frequent on tumor and vascular cells in BM and associated with distinct invasion patterns. Anti-integrin therapy could be a valid treatment option in patients with BM.
Interim safety analysis of a phase III trial with 5-FU, oxaliplatin, and docetaxel (FLOT) versus epirubicin, cisplatin, and 5-FU (ECF) in patients with locally advanced, resectable gastric/oesophagogastric junction (OGJ) cancer: The AIO-sto-0210 FLOT4 study.
2013-05-20

4079 Background: Perioperative ECF is a standard treatment for localized gastric/OGJ adenocarcinoma. However, 5-year survival rate remains below 40%. The FLOT regimen is an effective combination with pathologic response rates in the 15% range. This phase III study compares both regimens in resectable stages. Methods: Pts are stratified by different baseline criteria and randomized to either 3 + 3 perioperative cycles of ECF (epirubicin 50 mg/m 2 , d1; cisplatin 60 mg/m2, d1; 5-FU 200 mg/m2, d1-d21, qd21) or 4 + 4 cycles of perioperative FLOT (docetaxel 50mg/m 2 , d1; 5-FU 2600 mg/m2, d1; leucovorin 200 mg/m2, d1; oxaliplatin 85 mg/m2, d1, qd14). 5-FU can be replaced by capecitabine in the ECF-arm (ECX). Central pathology is performed. This is a preplanned safety analysis after 300 patients. Results: The ongoing studyhas enrolled 380 of planned 590 pts, so far. 305 pts were included in this analysis. Median age is 62 yrs; 78% of pts are male. The primaries were gastric in 44.9%, OGJ in 50.4% and not evaluable/documented in 4.7% of pts. 281 pts were eligible for safety analyses. Median no. of preoperative cycles was 3 and 4 with ECF/ECX and FLOT, respectively, 35.9% vs. 44.6% of pts (ECF/ECX vs. FLOT) started postoperative chemotherapy (ct) and 22.5% vs 33.1% received all planned cycles. Grade 3/4 neutropenia was observed in 28.0% of ECF/ECX and 45.3% of FLOT pts (p=.0026). Thromboembolic events occurred in 14.1% vs. 5.8% in pts with ECF/ECX vs. FLOT (p=.027). Serious adverse events occurred in 52.1% vs. 47.5% of pts with ECF/ECX vs. FLOT (p=.48). Preoperative delay/interruptions of ct were observed in 71.1% vs. 56.8% of pts with ECF/ECX vs. FLOT (p=.013). Dose modifications of preoperative ct were performed in 27.5% vs. 20.1% of treatment cycles with ECF/ECX vs. FLOT, respectively. 197 pts have undergone surgery so far. Severe surgical morbidity was similar in both arms (ECF/ECX, 19.8%; FLOT, 16.8%). Surgical mortality was observed in 4 and 2 pts with ECF/ECX and FLOT. Toxic deaths were observed in 1 pt each. Conclusions: Perioperative FLOT is feasible and safe. Clinical trial information: NCT01216644.