tbuckley/cabot-search huggingface dataset:
A phase 1 dose-escalation study of the oral selective inhibitor of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with heavily pretreated non-Hodgkin lymphoma (NHL).
Authors: Martin Gutierrez, Andre Goy, John C. Byrd, Joseph M. Flynn, Morten Sorensen, Peter Brown, Nashat Y. Gabrail, Michael Savona, Ian Flinn, Rachid C. Baz, Bijal D. Shah, Richard M. Stone, Eric Jacobsen, Vishal Kukreti, Roger E. Tiedemann, Tami Rashal, Mansoor Raza Mirza, Sharon Shacham, Michael Kauffman, John Kuruvilla
Journal: Journal of Clinical Oncology (2014)

8518 Background: KPT-330 (Selinexor) is a SINE XPO1 antagonist that forces nuclear retention and activation of >10 tumor suppressor proteins (TSP) and associated with reduction in c-myc and Bcl-XL. Anti-NHL activity was observed in murine models and in spontaneous canine aggressive lymphomas. Methods: Oral KPT-330 was given at 8-10 doses / 28-day cycle. XPO1 inhibition leads to rapid elevations in XPO1 mRNA, representing a pharmacodynamic (PDn) marker for KPT-330. Tumor biopsies were performed. Response evaluation was done in cycles 1, 2, and every 2 cycles. All pts had heavily pretreated NHL with progressive disease (PD) on study entry. Results: Thirty-two pts (18 M, 14 F; median age 68 yrs; ECOG PS 0/1: 9/23; median prior regimens: 3 range 1-11) received KPT-330 across 8 dose levels (3 to 60 mg/m2). Dosing at 60 mg/m2 twice weekly (BIW) is ongoing and MTD has not been reached. Cycle 1 (DLT period) Grade 3/4 events in >1 pt included thrombocytopenia (20%) and neutropenia (20%). The most common grade 1/2 AEs in cycle 1: anorexia (53%), nausea (50%), fatigue (50%), and vomiting (43%). Supportive care with appetite stimulants and anti-emetics diminished constitutional symptoms. Increases in XPO1 mRNA levels were observed at 4-48 hours, supporting BIW dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reduction, and apoptosis. Objective responses were observed in all histologies of NHL (Table). 5/16 pts have remained on therapy for an average of 9 months (>5-17) months without clinically significant toxicities. Conclusions: KPT-330 is generally well tolerated and can be administered over prolonged periods. The recommended phase 2 dose is ≥45 mg/m2BIW. Durable single agent activity was observed in heavily pretreated NHL pts, and phase 2 studies in DLBCL and Richter’s Syndrome are planned. Clinical trial information: NCT01607892.Response in 28 evaluable pts. NHL N PR+SD (%) PR (%) SD (%) [%Change in LN Size] PD Follicular (FL) 6 6 (100%) 1 (17%) 5 (83%) [-17% to -44%] – Mantle Cell 2 2 (100%) 1 (50%) 1 (50%) [-36%] – DLBCL 14 9 (64%) 3 (21%) 6 (43%) [-12% to -19%] 5 (36%) Transformed FL 3 1 (33%) 1 (33%) – 2 (67%) Richter's 3 3 (100%) 1 (33%) 2 (67%) [-22%] – Total 28 21 (75%) 7 (25%) 14 (50%) 7 (25%)
Survival of BCR-ABL positive and negative chronic myeloid leukemia: A propensity matched analysis of the Surveillance, Epidemiology, and End Results database.
Authors: Ranjan Pathak, Smith Giri, Michael Gary Martin, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2015)

e18053 Background: BCR-ABL negative chronic myeloid leukemia (CML) is uncommon without any previous largescale studies. Because of the genetic differences between BCR/ABL negative and positive CML, we compared their characteristics and outcomes in pre and post-imatinib era. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) 18 database and appropriate International Classification of Disease (ICD-O-3) histology codes to identify adult patients with BCR/ABL negative and positive CML diagnosed between 1973 and 2011. Propensity matching was performed using the MatchIt package of R v2.15.2 to create a matched dataset of BCR/ABL negative and positive CML in the pre-imatinib era (cases diagnosed before 2001) and the post-imatinib era (cases diagnosed after 2001).Kaplan Meier survival and multivariate analysis (Cox proportional hazard regression model) were done using SPSS v22.0. Results: 13,374 cases of BCR/ABL positive CML and 82 cases of BCR/ABL negative CML were identified. Patients with BCR/ABL negative CML, compared to BCR/ABL positive CML, were more likely to be older (69 vs. 60 years, p < 0.01) and diagnosed after 2001 (89% vs. 35.3%, p < 0.01). The median OS of BRC/ABL negative and positive CML was 15 months and 47 months respectively. OS was significantly lower among BRC/ABL negative CML (p < 0.01) but only during the post-imatinib era (p < 0.01). Multivariate analysis showed that OS was significantly lower among BRC/ABL negative (HR 2.15; 95% CI 1.57-2.92; p < 0.01) and with older age at diagnosis but better in more recent years. Gender and race did not influence OS. Conclusions: Our study demonstrates that the difference in OS between BRC/ABL positive and negative CML may not be the result of their intrinsic biology behavior, rather due to the powerful impact of tyrosine kinase inhibitors. Preclinical studies have indicated a possible therapeutic role of JAK inhibitors (ruxolitinib) and SRC kinase inhibitors (dasatinib) in select BRC/ABL negative CML. Identification of actionable mutations, development of novel therapies and improvement in transplant techniques have the potential to improve the outcomes of these patients.
Novel somatic <i>KIT</i> exon 8 mutation and response to imatinib in a patient with mucosal melanoma: A case report.
Authors: Suthee Rapisuwon, Kellie A Parks, Waddah B. Al-Refaie, Michael B. Atkins
Journal: Journal of Clinical Oncology (2014)

e20000 Background: Primary mucosal melanoma represent approximately 1.3% of all cases of melanoma in the US. The sinonasal location is the most common primary site. KIT gene mutations occur in 10-22% of patients. Tumor response to imatinib mesylate has been reported in about half of patients with tumors harboring mutations in KIT, Responses are almost exclusively restricted to tumors with KITexon 9 or exon 11 mutations. We present a case report of a patient with a sinonasal mucosal melanoma with a novel exon 8 mutation who had dramatic initial response to imatinib. Methods: A 63 year-old Caucasian female presented with a right paranasal mass. Subsequently she developed a large left anterior chest wall and other distant sites of metastases. She underwent treatment with ipilimumab, CTLA-4 antibody, without response. Mutation analysis performed on tumor found it to be BRAF V600 wild-type, but to contain a has KIT mutation at codon 443 (C443S). Imatinib treatment produced a dramatic initial response within 2 weeks, but disease progression was documented at 15 weeks. Results: Exon 8 somatic KIT mutations in mucosal melanoma or other human solid tumors have not been reported in literature; however such mutations have been reported in canine and feline mast cell tumors. Protein transcripts from exon 8 play an important role in structural and functional integrity of the extracellular domain of KIT. In pre-clinical studies, mutation in exon 8 leads to auto-phosphorylation, independent of KIT ligand, and constitutive activation of the tyrosine kinase. This biology perhaps explains the successful application of imatinib in animals with tumors harboring exon 8 KIT mutations and in our patient with mucosal melanoma. Conclusions: This report expands the population of patients with melanoma who might benefit from imatinib to those with somatic exon 8 KIT mutations. Such mutations should be looked for in patients with mucosal melanoma.
Potential risk of residential asbestos exposure: Japanese general screening study for asbestos-related diseases (JGSARD).
Authors: Nobuhiko Seki, Takuhiro Yamaguchi, Kenji Eguchi, Masahiro Kaneko, Masahiko Kusumoto
Journal: Journal of Clinical Oncology (2013)

e12541 Background: Currently, an argument about health risks by residential asbestos exposure as well as occupational asbestos exposure has been closed up in Japan. Therefore, the latest large-scale CT screening study reflective of a country's general situation of asbestos exposure will help citizens understand significant information about asbestos-related diseases. Methods: JGSARD is a prospective cohort study for the general population representative of Japan designed to evaluate the actual situation of asbestos exposure and the prevalence of asbestos-related diseases through chest radiography and low-dose CT (LDCT) at baseline and after 2 years of follow-up. From 2006 to 2008, 9810 subjects (mean age, 57 years; 54% male and 50% smokers) underwent baseline screening at 26 institutions in Japan. Lifetime self-reported history of asbestos exposure (SHAE) was obtained. Results: Occupational SHAE was definite and possible in 1103 (11.2%) and 1702 (17.3%) subjects, respectively, whereas residential SHAE was definite and possible in 262 (2.7%) and 931 (9.5%) subjects, respectively, although asbestos factory in their residential areas actually existed in 2870 (29.3%) subjects. The false negative rates of residential SHAE in all participants of this study (n=9810), those with pleural plaque on LDCT (n=264), and those with pleural plaque without occupational SHAE (n=83) were calculated as high value of 85.6%, 76.0%, and 87.9%, respectively. Presence of pleural plaque was significantly correlated with male (odds ratio [OR], 2.32), age 60 years and older (OR, 1.75), smoking (OR, 1.60), occupational or residential SHAE (OR, 3.92), residential period in asbestos factory area (OR every 10 years, 1.13), and asbestos-related work period (7 works identified). Lung cancer was identified in 29 (0.3%) subjects. Presence of lung cancer was significantly correlated with age 60 years and older (OR, 2.67) and presence of pleural plaque (OR, 4.17) regardless of occupational and residential SHAE. Conclusions: Our results indicate the potential risk of residential asbestos exposure and thus the importance of public relations and enlightenment for them among Japanese general population.
Phase II trial of a 2-hour infusion of gemcitabine plus carboplatin as first-line chemotherapy for advanced non-small cell lung cancer
Authors: N. Xu, P. Shen, C. X. Zhang, F. L. Yu, Y. H. Bao, M. G. Shi, S. Huang, J. Chen, J. W. Fang
Journal: Journal of Clinical Oncology (2006)

17099 Background: Prolonged infusion of gemcitabine have shown increased levels of the active triphosphate metabolite that theorically could increase the response rate and toxicity. The objectives of this study were to evaluated the efficacy and safety of this combination of using gemcitabine as a rate infusion of 10 mg/m 2 per min with carboplatin in front-line chemonaive patients with advanced NSCLC. Methods: Fifty-four chemonaive patients have been included. 44 were male and 10 female. Median age was 63 years (19–75). 13% had ECOG 0 and 53.7% ECOG 1 and 33.3% ECOG 2. 32 (59.2%) patients had adenocarcinoma, 13 (24.1%) squamous cell, 1 (1.9%) large cell carcinoma, and 8 (14.8%) others. Eight (14.8%) had stage IIIB and 46 (85.2%) stage IV. Treatment was consisted of 1200 mg/m 2 gemcitabine given as a 2-hour continuous infusion (10 mg/m 2 per min) on days 1 and 8 of each cycle an AUC 5 carboplatin as on day 1, repeating each cycle every 21 days. A total of 223 chemotherapy cycles were administered, with a median of 4 cycles per patient (range 1–6), and 15 (27.8%) patients received all six cycles. Results: Of the fifty-four patients enrolled, all were evaluated for toxicity (according to the WHO scale) and 51 assessed for response (according to the RECIST criteria), the overall response rate (ORR) was 41.2% (95% confidence interval, 28% to 57%), including two complete responses (CRs: 3.9%) and 19 partial responses (PRs: 37.3%). As per the intent-to-treat (ITT) analysis, the ORR was 38.9%. With a median follow-up time of 10.8 months, the median TTP was 5.0 months (range 3.7–6.3 months), median OS time was 11.5 months (range 9.9–13.1 months) and 1-year survival was 41.7% (95% CI 26% to 57%) and 2-year survival was 19.3% (4.4% to 34.2%).The main grade 3–4 toxicity consisted of neutropenia (55.6%) and thrombocytopenia (57.4%).Patients were required platelet transfusion in 27 cycles (12.1%) and haematopoietic growth factors support care in 56 (25.1%) cycles. No bleeding episodes were recorded. Grade 3 nausea/vomiting occurred in 5.6% and grade 1–2 skin rash occurred in 42.6%. Conclusions: Prolonged gemcitabine infusion combined with carboplatin is manageable tolerated and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment. No significant financial relationships to disclose.
Introduce Peanut-Containing Foods Early, NIH Panel Advises
Authors: Jennifer Abbasi
Journal: JAMA (2017)

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Phase 1 open-label dose escalation study of the dual SYK/JAK inhibitor cerdulatinib (PRT062070) in patients with relapsed/refractory B-cell malignancies: Safety profile and clinical activity.
Authors: Ian Flinn, Paul A. Hamlin, Donald K Strickland, Anjali Pandey, Matt Birrell, Greg Coffey, Janet Leeds, John T Curnutte, Jan Andreas Burger, Nina D. Wagner-Johnston, Manish R. Patel
Journal: Journal of Clinical Oncology (2015)

8531 Background: Inhibition of SYK and JAK independently has demonstrated clinical activity in patients with B cell malignancies. We present here an update on the first-in-human study of a dual SYK and JAK inhibitor, cerdulatinib, in patients with relapsed/refractory B cell malignancies. Methods: This was a 3+3 dose escalation study with 28-day cycles beginning at 15 mg once daily oral dose. PK, PD, and safety were monitored. Response was assessed by standard criteria. Results: No dose-limiting toxicities have been reported to date. As of January 15th, 2015, a total of 25 patients with CLL/SLL or B cell NHL were dosed. Median age was 72 years (23-85) and median prior therapies was 4 (1-6). Treatment emergent AEs of ≥ grade 3 regardless of causality were: grade 3 hyperkalemia (n = 1) and anemia (n = 1) and grade 5 Pneumocystis pneumonia (PCP; n = 1) at 30 mg total daily dose; grade 3 fatigue (n = 1) and AST increase (n = 1) were observed at the 45mg dose. The patient with grade 3 AST had tumor progression to the liver. PK is suitable for once daily dosing with a half-life of 12-16 hours and a 2:1 peak-trough ratio. Saturating inhibition of SYK and JAK in circulating lymphocytes (80-90% inhibition) and serum inflammation markers (e.g., β2M, CRP, CCL4; 50-90% inhibition) occurs at plasma concentrations of ~ 0.6-1µM, achieved at Cmin of the 40mg dose. At 30mg once daily, one partial response was observed in a CLL patient with a 17 p deletion who relapsed on six prior regimens and was intolerant of a PI3K inhibitor. At the 45mg dose, two partial responses were observed at completion of the second cycle of therapy: the first in a follicular lymphoma patient with 3 prior regimens and the second in a CLL patient with 4 prior regimens. Dose escalation continues to identify the maximum tolerated dose. Conclusions: Cerdulatinib continues to demonstrate a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. The clinical responses seen at the 45mg dose level support further development. A phase II expansion study at this dose is planned to begin in the first quarter of 2015. Clinical trial information: NCT01994382.
Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.
Authors: Manuel Hidalgo, Antonio Calles, Dejan Juric, Rodrigo Dienstmann, Desamparados Roda Perez, Wells A. Messersmith, George R. Blumenschein, José Baselga, Josep Tabernero, Andres Cervantes-Ruiperez, Antonio Jimeno, Denise Jin, Shuang Bai, Pavel Gurevich, Ihsan Nijem, Scott N. Holden, John D Davis, Wendy Halpern, Andrea Pirzkall, Yan Xin
Journal: Journal of Clinical Oncology (2012)

2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, 4, 10, 15, 22, and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w) of the phase I study. Patient demographic data and other relevant clinical covariates were evaluated in the population analysis. PK simulation of 1000 subjects with a log-normal BW distribution was performed to compare the inter-individual variability of MEHD exposure following fixed or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK. In the noncompartmenal analysis, the apparent clearance (CL) decreased in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30 mg/kg) and approached linearity at doses &gt;10 mg/kg (q2w). In the population analysis, the PK profile of MEHD was well described by a two compartment model with linear and nonlinear clearance. The target-mediated clearance was consistent with that of anti-EGFR antibodies. The nonspecific CL and central volume of distribution (V1) values were approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a moderate effect on V1, but not on CL. PK simulations suggest that, compared with BW-based dosing, fixed dosing would result in less inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650 mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions: The dual-action antibody MEHD demonstrated PK consistent with anti-EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule is supported.
MRI-based vessel function maps for high-resolution differentiation between tumor and nontumoral tissues in brain tumor patients.
Authors: Leor Zach, David Goez, Yuval Grober, David Last, Dianne Daniels, Chen Hoffmann, Dvora Nass, Ouzi Nissim, Roberto Spiegelmann, Zvi R Cohen, Yael Mardor
Journal: Journal of Clinical Oncology (2012)

2078 Background: Changes in enhancement seen in post treatment brain MRIs in primary and secondary brain malignancies often mimic tumor progression (pseudoprogression, radiation necrosis). Conventional MRI cannot differentiate tumor progression from treatment related effects resulting in suboptimal patient management. Methods: The application of delayed contrast extravasation MRI for depicting unique vessels characteristics with high resolution and high sensitivity to subtle BBB disruption is demonstrated in 17 GBM and 15 brain metastases patients undergoing standard chemoradiation and radiosurgery respectively. Results: 2 primary vessel function populations were defined: a slow population where contrast clearance from the tissue was slower than accumulation, and a fast population where clearance was faster than accumulation. Ten stereotactic biopsies acquired from GBM patients showed complete correlation with the maps, confirming the discrimination between fast population regions, reflecting morphological active tumor and slow regions reflecting necrosis/treatment-induced changes. Typical fast population vessel morphology consisted of proliferating endothelial cells, dilated lumen, peri vascular fibrosis and glumeroloid vessels, while slow regions consisted of necrotic vessels, in agreement with the observed MRI vessel function. The fast component volume 3 weeks post treatment was significantly correlated with the fast volume 4 (r 2 =0.84, p&lt;0.0005) and 6 months (r 2 =0.84, p&lt;0.01) later, suggesting early prediction of response. Brain metastases histology showed similar results: 5 brain metastases with a fast population component were confirmed histologically to contain morphologically active tumor. One metastasis consisting of the slow population only significantly decreased in volume in the following MRIs. Conclusions: These results demonstrate the feasibility of applying our delayed contrast extravasation high resolution function vessel maps for improving patient management by clearly depicting tumor and non-tumoral tissues in patients with primary and secondary brain malignancies undergoing standard chemoradiation or radiosurgery.
Targeting the CD44/EMT phenotype for improving response to therapy in pancreatic cancer models.
Authors: Katherine Wei-Lin Chang, Shujie Zhao, Chen Chen, Lin Cao, James W Freeman
Journal: Journal of Clinical Oncology (2015)

e15291 Background: Heterogeneity of cancer cells within tumors and established cancer cell lines is well known. We found that CD44, a non-kinase transmembrane receptor that binds hyaluronan, showed differences in expression levels and in expression of isoforms in pancreatic ductal adenocarcinoma (PDAC) cell lines. Here we investigated the role these differences have on phenotype, tumorigenic properties and response to gemcitabine. Methods: Cells from CFPAC-1 were sorted, by flow cytometry, on the basis of their expression level of CD44 and these cells are referred to as CD44high and CD44low. CD44high cells expressed high levels of predominantly the CD44 standard isoform (CD44s) as confirmed by Western blotting, RT-PCR, q-PCR and DNA sequencing. CD44low expressed mainly CD44 variant isoforms (CD44v) including CD44v3-6 and CD44v8-10. CD44high cells possessed an epithelial to mesenchymal transition (EMT) phenotype; whereas, CD44lowmaintained an epithelial phenotype. Results: In vitro studies showed that CD44high/EMT cells were more invasive, showed a reduced response to gemcitabine, and formed tumorspheres. Knock down of CD44 expression in CD44high cells partially reversed the EMT phenotype, inhibited invasion and increased response to gemcitabine. The role of the CD44high phenotype played in tumorigenicity was also confirmed in a separate PDAC cell line, ASPC-1. Knockdown of CD44 in ASPC-1/CD44high cells also reduced invasion and increased response to gemcitabine. Tumors from mice orthotopically implanted with CD44high/EMT cells grew significantly faster and showed an increase in desmoplasia and developed more liver metastases. In treated groups, mice received gemcitabine beginning 2 weeks after tumor implantation. Interestingly, tumors from CD44low mice showed little or no progression through 20 weeks. In the CD44high group gemcitabine suppressed growth initially compared to untreated controls. However, after an initial delay of tumor progression for 10 weeks, CD44hightumors showed escape from treatment with exponential growth. Conclusions: Further studies that combine targeting CD44high/EMT phenotype with chemotherapy are needed to determine if this strategy will improve patient survival.