bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.
Authors: Sheikh Nadeem A. , Wesley Johnna D. , Perdue Nikole , Stewart Frances P. , Fong Lawrence 
Published: March 2020

2563 Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). NeoACT (Study P07-1) was undertaken to investigate neoadjuvant sipuleucel-T treatment in subjects with localized prostate cancer. Methods: In this open-label, phase 2 study (NCT00715104), subjects with localized prostate cancer received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy (RP). Following RP, subjects were randomized 1:1 to receive / not receive a sipuleucel-T booster infusion 12 weeks post-RP. Cellular composition, antigen presenting cell (APC) activation, cytokines, and T and B cell activation were profiled before and after each culture with PA2024, the fusion protein containing prostatic acid phosphatase used to generate sipuleucel-T. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T, and 15 subjects received a booster infusion. Consistent with sipuleucel-T in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first (p<0.001). The expression of early T cell activation markers (CD134, CD137, CD278 and CD279) were increased in pre-culture cells obtained after the first infusion, and further increased after culture. Activated mature B cells (CD20+CD27+IgD+CD86+) increased following culture in all 3 products (p<0.01); memory B cells (CD20+CD27+IgD-CD86+) were progressively increased following the first infusion (p<0.05 third vs. first product). TNF-α, IFN-γ, IL-2 were secreted at higher levels during culture of the second and third products (all p<0.001). The observed increases in CD54 upregulation, early T cell activation markers, and memory and activated mature B cells were maintained at booster treatment. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that was consistent with boosting of an immune response primed with the first infusion. Immune activation was maintained at the booster infusion 3 months following initial sipuleucel-T treatment.
Is cigarette smoke associated with increased catabolism of gemcitabine in patients with advanced solid tumors?
Authors: O'Malley Meaghan Working , Daignault Stephanie , Healy Patrick N. , Schmidt Lindsay A. , Ramnath Nithya 
Published: March 2020

2602 Background: Cigarette smoking can accelerate chemotherapy metabolism and result in lower plasma concentrations of the chemotherapeutic agent. Reduced drug levels may lead to undertreatment in smokers and, conversely, increased treatment-related neutropenia in nonsmokers. Methods: An IRB-approved retrospective chart review was performed on 151 patients with solid tumor malignancies who received gemcitabine alone or in combination with oral chemotherapy agents from July 1, 2009 to June 30, 2011 at the University of Michigan. Using logistic regression, we compared toxicity, including neutropenia, and smoking history measured in pack-years in smokers vs. nonsmokers to ascertain whether cigarette smoking is an independent factor predictive of toxicity to gemcitabine. Results: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary (15.2%). Most patients had advanced disease (stage III-IV; 78.1%); specifically, of the pancreatobiliary cohort (PB; n=107), 77.6% patients had stage III-IV disease. Within the PB cohort, most patients were “ever” smokers as compared to “never” smokers (60.7% vs. 39.3%). Logistic regression of this cohort showed that current smokers had decreased CTC-AE grade 3-4 neutropenia vs. never smokers (OR 0.667; 95% CI [0.156-2.859]). This effect was more pronounced with higher pack-year history: smokers with >50 pack-years had even less neutropenia as compared to never smokers (OR 0.333; 95% CI [0.065-1.699]). Further statistical analysis of subgroups was not performed due to small sample size. Conclusions: Smokers with pancreatobiliary malignancies receiving gemcitabine had less treatment-related neutropenia as compared to never smokers, a finding that was more pronounced as pack-years increased. Decreased toxicity, including neutropenia, may be due to increased metabolism and drug clearance as a result of smoking. This may lead to potential undertreatment of smokers and, conversely, increased treatment-related toxicity in never smokers. A prospective clinical trial is needed to further elucidate this correlation, and is currently being designed.
Phase I study of intravenous PI3K inhibitor BAY 80-6946: Activity in patients (pts) with advanced solid tumors and non-Hodgkin lymphoma treated in MTD expansion cohorts.
Authors: Lotze Michael T. , Appleman Leonard Joseph , Ramanathan Ramesh K. , Tolcher Anthony W. , Beeram Muralidhar , Papadopoulos Kyriakos P. , Rasco Drew Warren , Weiss Glen J. , Mountz James M , Toledo Frederico G.S. , Alvarez Rene J , Oborski Matthew J , Rajagopalan Prabhu , Jeffers Michael , Roth Diane , Dubowy Ronald L. , Patnaik Amita 
Published: March 2020

3019 Background: BAY 80-6946 (BAY) is a potent and highly selective reversible pan-Class I PI3K inhibitor, previously reported to be tolerated as a 1-hr infusion at a dose of 0.8 mg/kg on days 1, 8 and 15 every 28 days (MTD). Additional pts were treated in MTD expansion cohorts to assess safety, PK, biomarkers and clinical benefit in selected tumor types, as well as safety in Type 2 diabetics. Methods: To date, 23 nondiabetic pts with solid tumors and 5 with follicular lymphoma (FL) received BAY at the MTD, until disease progression or unacceptable toxicity. Tumor types were selected for high frequency of PIK3CA mutation, including breast cancer (BC; 16), endometrial (3), gastric (2), GU transitional cell (1) and ovarian clear cell (1). Partial enrichment for PIK3CA mutation was achieved by analysis of plasma DNA. 3 diabetic pts have been enrolled, at starting dose of 0.4 mg/kg. PK was done after the 1st and 3rd doses. FDG-PET/CT scans were done at baseline and 48 hrs after the 1st dose for pharmacodynamic assessment. Results: Safety and tolerability assessments confirmed MTD. There were no 1st cycle DLTs. Almost all nondiabetic pts had acute Grade 2/3 hyperglycemia (HG) following each dose; at least 10 of them received insulin for 1-3 days post dose. Hypertension (HTN) lasting < 24 hrs was common in pts with preexisting HTN, and manageable. 2 FL pts developed interstitial pneumonitis (IP) after cycles 2 and 3, both responsive to steroids. Diabetic pts tolerated 0.4 mg/kg. Tumor SUVmax consistently fell at 48 hrs. 3 of 4 FL pts had partial response (PR) after 2 cycles, with 2 confirmed PR pts on BAY for 10+ and 8+ mos. 2 BC pts showed PR , 1 confirmed. PIK3CA mutation (n=7) does not appear to correlate with response. Average T1/2 was 36 hrs. Observation of high Cmax in very obese pts led to recommended maximum dose of 65 mg. Conclusions: BAY induced PRs in pts with BC and FL. The acute toxicities of HG in most pts and HTN in some are manageable, and IP has been limited to 2 lymphoma pts and is responsive to steroids. The observed clinical activity of BAY, along with its acceptable safety profile, provide a rationale for the ongoing development of BAY in combination with cytotoxic and targeted agents.
Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally QD to patients with advanced solid tumors.
Authors: Daniele Gennaro , Ranson Malcolm , Blanco-Codesido Montserrat , Dean Emma Jane , Shah Krunal Jitendrakumar , Krebs Matthew , Brunetto Andre , Greystoke Alastair , Johnston Claire , Kuznetsov Galina , Matijevic Mark , Mistry Bipin , de las Heras Begona , Molife L Rhoda 
Published: March 2020

3030 Background: Golvatinib is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed preclinical evidence of anti-tumor activity. This phase 1 study was performed to determine the MTD, safety, PK, PD and preliminary activity of golvatinib. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, ≥ 18 years (yrs) and adequate organ function were eligible. Golvatinib was administered orally, once daily (QD), continuously. Blood samples for PK and PD analysis were collected at multiple time-points. Mandatory tumor biopsies for PD analysis were taken pre and post Cycle 1 in an expanded MTD cohort. Results: 34 pts (M/F: 21/13; median age 63.5yrs [range 32-78]) were treated at 6 dose levels: 100, 200, 270, 360, 450 and 400 mg. Tumor types were colorectal (n=15), lung (n=4), renal (n=4), esophageal (n=2), melanoma (n=2) and others (n=7). Three DLTs were observed: Gr3 GGT and alkaline phosphatase (n=1; 200mg) and repeated Gr2 (n=1) and Gr3 (n=1) fatigue, both at 450mg. The MTD was determined to be 400 mg QD. Frequently occurring adverse events ([AEs]; all grades) were fatigue: 68% (Gr3: 15%), diarrhea: 65%, nausea: 62%, vomiting: 53%, decreased appetite: 47% (Gr3: 9%), ALT increase: 38% and AST increase: 23%. No Gr4 AEs were observed. Best response was stable disease in 6 pts lasting >84 days. PK showed high variability and plasma concentration increased with dose. The Cmax was reached within a median time of 4 hours. Plasma PD analysis showed an increase in soluble c-Met and Ang 2 levels after golvatinib treatment. Tumor PD analysis in 5 pts at 400 mg demonstrated a baseline elevated MET gene copy number, with c-Met overexpression and post treatment decline in phospho(p)-c-Met expression in 1 pt; post-treatment decline in p-c-Met in a 2nd pt, and post-treatment decline in p-ERK in a 3rd pt. Conclusions: Golvatinib at an MTD of 400 mg QD has manageable toxicity. Preliminary PD analysis demonstrated evidence of c-Met target modulation. Further evaluation will continue in phase 2 combination studies.
NRAS mutations in patients with advanced cancers treated with target-based therapies in early-phase clinical trials.
Authors: Madhusudanannair Vinu , Janku Filip , Falchook Gerald Steven , Hong David S. , Wheler Jennifer J. , Naing Aung , Fu Siqing , Piha-Paul Sarina Anne , El-Osta Hazem Edmond , Luthra Rajyalakshmi , Tsimberidou Apostolia Maria , Kurzrock Razelle 
Published: March 2020

3106 Background: NRAS mutations in cancers increase MAPK signaling. It is plausible that NRAS mutations may be associated with sensitivity to drugs targeting the MAPK pathway. Methods: Tumors from 689 patients with advanced cancers referred to the Clinical Center for Targeted Therapy (phase I program) were screened in a CLIA-certified laboratory for NRAS mutations and if feasible, for PIK3CA, KRAS, BRAF mutations and PTEN aberrations. Whenever possible, patients with NRAS mutations were treated with agents targeting the RAF-MEK pathway. Results: Of the 689 patients, 58 (8%) had NRAS mutations. NRAS mutations were most prevalent in melanoma (26/170, 25%), thyroid (5/26, 19%), endometrial (2/27, 7%), non-small cell lung (1/31, 3%), ovarian (1/60, 2%) and colorectal cancers (1/74, 1%). NRAS mutations were not seen in any of the tested head and neck squamous cell cancers (n = 44); sarcomas (n = 41) and breast cancers (n = 25). None (0/62, 0%) of the patients tested for KRAS had simultaneous NRAS and KRAS mutations, and only 2/42 (5%) tested for BRAF had simultaneous NRAS and BRAF mutations. Of 58 patients with NRAS mutations, 14 (24%) were enrolled in trials that included MEK axis inhibitors. Of these 14 patients, 13 had melanoma and 1 had ovarian cancer and 4/14 (29%) demonstrated tumor shrinkage >10% from baseline. In comparison, only 22/187 (12%) patients with wild-type/unknown NRAS, KRAS and BRAF treated on the same trials demonstrated tumor shrinkage >10% (p=0.086). Conclusions: NRAS mutations are diagnosed in variety of advanced cancers. Patients with NRAS mutations demonstrated a trend to better antitumor activity with MEK axis inhibitors compared to patients without NRAS, KRAS or BRAF mutations. Further studies are warranted to delineate the role of NRAS mutations in patients treated with MEK axis inhibitors.
Use of next-generation sequencing (NGS) to detect a novel ALK fusion and a high frequency of other actionable alterations in colorectal cancer (CRC).
Authors: Ross Jeffrey S. , Lipson Doron , Sheehan Christine E , Otto Geoff , Yelensky Roman , Parker Alex , Jarosz Mirna , Juhn Frank , Brennan Tina , Downing Sean , Donahue Amy , Balasubramanian Sohail , Palmer Gary A. , Miller Vincent A. , Stephens Philip , Cronin Maureen T. 
Published: March 2020

3533 Background: We hypothesized that NGS could identify genomic alterations that guide selection of targeted therapies and discover novel drug targets for primary and metastatic CRC. Methods: DNA was extracted and sequenced from 4 X 10 μ FFPE sections from 40 (32 primary and 8 metastatic) CRCs obtained from 2004-10 (52% male; 48% female; mean age 60 years; 10% Stages I/II; 40% Stage III; 40% Stage IV; 10% Stage unknown) using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). 2574 exons of 145 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: NGS revealed 125 genomic alterations in 39/40 tumors (mean 3.1, range1-7) in 21 genes, including 80 base substitutions (64%), 39 insertions/deletions (31%), 4 CNAs (3%) and 2 gene fusions (1.6%). TP53 and APC were altered in 80% (32/40) and 67.5% (27/40) of CRCs respectively, with both mutated more frequently than reported in COSMIC. Alterations associated with potential sensitivity to targeted therapies were identified in 21 (52.5%) of CRCs including: 10 KRAS (TK/MEK inhibitors), 6 BRAF (BRAF inhibitors), 5 FBXW7 (mTOR inhibitors); 2 PIK3CA (PI3K/mTOR inhibitors); 2 BRCA2 (PARP inhibitors); 2 GNAS (MEK/ERK inhibitors) and 1 CDK8 (CDK inhibitors). In 1 CRC, a 5.2 Mb tandem duplication generated a novel C2orf44-ALK gene fusion starting at the canonical exon 20 recombination site previously reported for the majority of ALK gene fusions. cDNA sequencing identified an 90-fold increase in 3’ ALK expression, suggesting the C2orf44-ALK fusion results in ALK kinase domain overexpression and contains the same intracellular domain as other ALK fusions including the ALK inhibitor sensitive EML4-ALK. Conclusions: NGS of broad, cancer-related gene content from FFPE CRC samples uncovered an unexpectedly high frequency of genomic alterations, many of which may be clinically actionable by informing treatment decisions, including a novel ALK gene fusion. This previously unrecognized subset of CRC patients may be candidates for clinical trials of crizotinib or other ALK inhibitors.
Phase I study of EMD 525797 (DI17E6), an antibody targeting ανβ integrins, in combination with cetuximab and irinotecan, as a second-line treatment for patients with k-ras wild-type metastatic colorectal cancer.
Authors: Elez Elena , Kocáková Ilona , Hoehler Thomas , Martens Uwe Marc , Bokemeyer Carsten , Van Cutsem Eric , Fram Robert J , Bernard Laurence , Tabernero Josep 
Published: March 2020

3539 Background: EMD 525797 is a humanized monoclonal antibody that specifically targets all αν integrins, including ανβ1, ανβ3, ανβ5, ανβ6, and ανβ8. In colorectal cancer (CRC), ανβ3 is highly expressed on tumor-associated vessels, and ανβ5 is strongly expressed on tumor cells, vessels, and stromal cells. Overexpression of ανβ6 is associated with a significant reduction in median overall survival. Methods: Safety, tolerability, and anti-tumor activity of escalating doses of EMD525797 in combination with irinotecan and cetuximab were assessed in patients (pts) with metastatic CRC who had failed first-line fluoropyrimidine/oxaliplatin-containing chemotherapy. Pts received IV infusions over 1 hour of 250, 500, 750, and 1,000 mg EMD 525797 every 2 weeks in combination with irinotecan at 180 mg/m2 IV every 2 weeks and cetuximab at 400 mg/m2 on Cycle 1, Day 1 and then 250 mg/m2 IV weekly. A standard 3+3 trial design was used. Three pts were enrolled at each dose level and if no dose limiting toxicities (DLTs) were observed, pts were enrolled at the next dose level. An additional 3 pts were added if 1 of the initial 3 pts in the cohort experienced a DLT. Results: A total of 16 pts received treatment.No DLTs were observed at any dose of EMD 525797 in combination with irinotecan and cetuximab. Serious adverse events related to EMD 525797 included Grade 3 hypokalemia and tachyarrhythmia. Dosing was well tolerated over treatment intervals as long as 18 months. Objective responses included 1 partial response (PR) at 250 mg; 1 complete response and 1 PR at 750 mg; and 2 PRs at 1,000 mg. Two pts had prolonged stable disease lasting longer than 11 weeks at 750 mg. Anti-tumor activity was observed in pts who had failed anti-VEGF therapy in combination with first-line chemotherapy. Conclusions: The combination of EMD 525797 with irinotecan and cetuximab was well tolerated and has anti-tumor activity. Further evaluation of this regimen is warranted and is underway in an open-label, randomized phase II study of two doses of EMD 525797 (500 and 1,000 mg) combined with irinotecan and cetuximab that are compared with standard irinotecan and cetuximab.
Primary side of origin affects the outcome of mCRC patients treated with first-line FOLFIRI plus bevacizumab independently of BRAF status and mucinous histology.
Authors: Loupakis Fotios , Yang Dongyun , Zhang Wu , Cremolini Chiara , Wakatsuki Takeru , Salvatore Lisa , Antoniotti Carlotta , Aprile Giuseppe , Schirripa Marta , Ricci Vincenzo , Lucchesi Sara , Masi Gianluca , Maus Martin Karl Herbert , Lonardi Sara , Ning Yan , El-Khoueiry Rita , Falcone Alfredo , Lenz Heinz-Josef 
Published: March 2020

3549 Background: Several studies tried to address the question of whether primary site of CRC could affect the outcome. Those analyses were limited by small sample size numbers and/or high degree of heterogeneity in stage and received treatments and/or limited information regarding molecular and pathologic features. Mucinous histology and BRAF mutations are more frequent in right-sided tumors and are both associated with worse outcome in the metastic setting. Methods: the analysis was conducted on a database of 455 mCRC prospectively enrolled in a pharmacogenetic translational study. Patients (pts) were treated with FOLFIRI/bevacizumab. Pts were excluded if data regarding mucinous histology and/or BRAF mutational status were lacking or if affected by synchronous right and left-sided tumors. Results: 200 pts were identified and included in the study. Mucinous histology, BRAF mutation and right-side primary were found in 35 (17.5%), 14 (7%) and 56 (28%) patients respectively. Right-side tumors were more frequently BRAF mutated (p<0.001) and the association was still significant when adjusting for mucinous histology (p=0.001). There was a trend in the association between mucinous and side (p=0.082). At a multivariate analysis, pts with right-side primary were at higher risk of progression (HR=1.88 [95%CI: 1.25-2.84], p=0.0026) and death (HR=2.07 [95%CI: 1.23-3.49], p=0.006). At a prespecified analysis in the subgroup of non-mucinous and BRAF wild-type tumors, pts with right-side primary achieved median PFS and OS of 10.0 and 28.9 mos compared to 13.0 and 47.6 mos of left-side (PFS, right vs left: HR=1.87 [95%CI: 1.19-2.91], p=0.003; OS: HR=1.91 [95%CI: 1.07-3.39], p=0.022). This was again confirmed in a multivariate model. Conclusions: These data underline a possible strong impact of side on the outcome of mCRC treated with first-line FOLFIRI plus bevacizumab. To give a biological explanation for these results, a GWAS on germinal DNA and gene-expression analyses on tumors are ongoing. In order to clarify the prognostic vs predictive role to antiangiogenic treatments of this feature analyses from 2 phase III randomized trials have been planned.
Improved early prediction of individual prognosis for patients with mCRC: Joint modeling of tumor shrinkage with volume data for PFS and OS.
Authors: Mansmann Ulrich Robert , Laubender Ruediger Paul , Sartorius Ute , Giessen Clemens Albrecht , Graser Anno , Heinemann Volker 
Published: March 2020

3603 Background: Piessevaux et al. (ESMO 2010) proposed a decrease in RECIST-based tumor size of 20% at week 8 following 1st-line therapy for mCRC as a predictor of clinical outcome (PFS and OS). We expanded upon this idea (ASCO GI 2012). A tumor volume algorithm was developed providing a better approximation to true tumor volume by using both the longest and the longest orthogonal diameters of a target lesion. In this study we compare the quality of early prediction-based individual patient prognosis based on tumor change according to either RECIST or the tumor volume algorithm. Methods: The prognostic method is combined with the volume algorithm and applied to the data from 2 studies (OPUS, n=337; CRYSTAL, n=1198) and 4 treatment regimens (FOLFOX4 +/- cetuximab and FOLFIRI +/- cetuximab), in patients with mCRC. The influence of the treatment regimen on early PFS and OS prognosis is studied by joint modeling. The quality of early prognosis depending on the tumor size assessment used is compared by the logarithmic scoring rule. Results: Individual volume shrinkage and baseline volume are considered prognostic factors. Individual predictions depend on the chemotherapy administered and whether cetuximab is added. Equivalent tumor baseline volumes and early volume changes, predict an up to 20% higher 1 year (y) PFS and 2y OS rate for FOLFIRI than for FOLFOX. The addition of cetuximab to standard chemotherapy (CT) translates into a mean increase in shrinkage of 10% resulting in an improvement in 1y PFS rates of 23% and in 2y OS rates of 18%. The quality of individual prediction over the 4 regimens is combined in one logarithmic (log) score. The log score for the RECIST-based prediction is 2.45 which is significantly higher than that for the volume-based prediction of 1.97 (p<0.0001). Lower scores correspond to a better prediction. Conclusions: The tumor volume algorithm enables a more precise prediction of individual patient PFS and OS than RECIST-based tumor assessments. Based on early tumor changes for CT, +/- cetuximab, it is possible to calculate quantitative information on a patient’s prognosis. The model has high potential to guide individual clinical decision making for mCRC patients.