tbuckley/cabot-search huggingface dataset:
Treatment of angiosarcoma with pazopanib and paclitaxel: Results of the phase II trial of the German Interdisciplinary Sarcoma Group (GISG-06 EVA) study.
Authors: Daniel Pink, Sebastian Bauer, Thomas Brodowicz, Peter Reichardt, Bernd Kasper, Stephan Richter, Peter Hohenberger
Journal: Journal of Clinical Oncology (2018)

11570 Background: Angiosarcomas (AS) account for 2-3% of all soft tissue sarcomas. About 60% develop at the skin, and radiation-induced AS following breast cancer therapy represent a characteristic feature. In metastatic or locoregionally advanced AS paclitaxel may induce tumor response. Data also show positive effects of VEGF-inhibiting drugs in AS patients. Thus, the combined application of chemotherapy and TKI seems warranted. Methods: This multicentre, open, prospective, single-armed phase II trial (NCT02212015) evaluates efficacy and safety of combined pazopanib (800mg/d) and paclitaxel (70mg/msq d1, 8, 15 of a 28d cycle) in advanced or metastatic AS. Primary endpoint is PFS at 6 mos. after start of therapy. Statistical analysis looks for 6 m-PFS > 35% using RECIST 1.1. The trial is conducted in two steps with an interim futility analysis. Twenty-six patients were recruited (23 f, 3 m, median age 60.5 yrs), ECOG 0/1: n = 20/6 (80%/20%), 5 pts had local tumor progression, 21 pts (80.8%) showed metastatic disease, tumor description see table 1. Results: At interim analysis, the full analysis set consisted of 26 pts who received study medication at least once. The number of successes (6-m PFS yes) was n = 12 (46%). We had to adapt type-I-error for overrunning the pre-specified interim sample size, prompting a boundary of 17/26 pts with 6-m PFS, which the study did not meet (2-sided Clopper-Pearson CI). The formal decision was to stop the trial for futility. Analysing the non-responders showed that none of pts with hepatic involvement and 2nd AS after total body irradiation (TBI) did profit from study therapy. Conclusions: Combined paclitaxel and pazopanib is an active treatment in AS particularly in tumors located superficially. Patients with visceral metastases and those with hepatic angiosarcoma after TBI did not respond. The study protocol is about to be amended with refined inclusion citeria. Clinical trial information: NCT02212015.Location of AS: skin. 17 ( 65.4%) Loc. of AS: visceral/deep 12 ( 46.2%) of loc. skin: chest/chest wall 13 ( 76.5%) of loc. visc/deep: liver 5 ( 41.7%) of loc. visc/deep: other 6 ( 50.0%) Haemangiosarcoma 22 ( 84.6%) Lymphangiosarcoma 4 ( 15.4%) 1ry AS 13 ( 50.0%) 2ndary AS 13 ( 50.0%)
Addition of HSP90 inhibitor onalespib to crizotinib prior to progression in patients with ALK-pos NSCLC: Results of a randomized phase 2 study.
Authors: Jong-Seok Lee, Ji-Youn Han, Myung-Ju Ahn, In-Jae Oh, HyeRyun Kim, Dae Ho Lee, Erin Marie Bertino, Santiago Viteri Ramirez, Nathan A. Pennell, Antoinette J. Wozniak, Joan H. Schiller, Chester Lin, Harold N. Keer, Mohammad Azab, Benjamin Besse, D. Ross Camidge
Journal: Journal of Clinical Oncology (2016)

9059 Background: Crizotinib (C) was the first approved ALK inhibitor for use in in ALK positive (pos) NSCLC, but resistance ultimately develops through both ALK-related and other signaling pathways. Onalespib (AT13387; O) is an HSP90 inhibitor which can interfere with the maturation of many client proteins, including ALK. In ALK-driven preclinical models, O when combined with C, delays the emergence of resistance, providing the rationale for this phase 2 study. Previously, Besse, et al (Ann Onc[2014]25[suppl_4]iv426-iv470), noted that C + O can be safely combined at effective doses of each and some activity was seen. Here we report the results of a randomized study comparing C+ O to C-alone in ALK-pos NSCLC patients (pts). Methods: This was an open-label, randomized, controlled study in which pts with ALK-pos NSCLC receiving C without progression, ECOG PS 0-2 and adequate organ function were randomized 1:1 to continuing C (250 mg BID) vs. adding O (220 mg/m2 D1,8,and 15 Q28 D) to the treatment regimen. C-only pts were allowed to crossover to C+O at progression. The primary endpoint was Progression-free survival (PFS) and secondary endpoints included Overall Survival (OS), Safety, and Objective Response Rate (ORR). Results: Pts (68 C/68 C+O) were generally balanced for age (50.4/55.8), Sex (50%M/34%M), ECOG 0-1 (93% /95%), Brain mets (48%/43%), and prior systemic therapy (68%/66%), respectively. PFS analysis showed no difference between the groups (median PFS C: 266 days/C+O: 269 days, HR 1.025). ORR slightly favored the C+O group (55.4% vs. 45.3%), and OS was not mature. The C+O treatment produced more ≥ Gr.3 AEs (51% vs. 29%, most common diarrhea, nausea, and vomiting), however there was no increase in the percent of pts discontinuing due to AE (4% vs. 5%). Conclusions: This is the first randomized study to clinically test the hypothesis that early dual inhibition of an HSP90 client protein by a kinase inhibitor combined with an HSP90 inhibitor may delay the emergence of resistance and prolong PFS. Despite previous promising non-clinical studies, while O + C could be safely combined, the combination did not delay the emergence of clinical resistance in ALK-pos NSCLC. Clinical trial information: NCT01712217.
Cost-utility analysis of aprepitant for patients who truly need it in a Japanese health care setting.
Authors: Ikuto Tsukiyama, Masahiko Ando, Sumiyo Tsukiyama, Masayuki Takeuchi, Masayuki Ejiri, Yoshihiro Yamamoto, Nobuhiro Asai, Hiroko Saito, Ichiro Arakawa, Tadao Inoue, Katsuhiko Matsuura, Akihito Kubo
Journal: Journal of Clinical Oncology (2016)

e18243 Background: Neurokinin 1 receptor antagonists (NK1RAs) are recommended to prevent chemotherapy induced nausea and vomiting (CINV) for patients who receive highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) regimens of anthracycline plus cyclophosphamide. We reported that aprepitant (APR) was not needed to control CINV in 57% or 89% of patients who received HEC or MEC, respectively. To elucidate the cost-effectiveness of APR, we performed cost-utility analysis in these patients according to the necessity of APR. Methods: A decision analytic model was developed according to the necessity of APR and CINV responses in both acute and delayed phases. A patient who needed aprepitant was defined as a patient who experienced CINV and received aprepitant for therapeutic intent and/or received aprepitant for prophylactic intent in the subsequent courses of chemotherapy. Probabilities of health states and actual medical costs were derived from the results of the above mentioned trial. Utility values of each health states were quoted from the previously published reports. Incremental cost effectiveness ratios (ICERs) were calculated in HEC and MEC according to the necessity of APR. Analysis conducted on the national medical insurance payer perspective. All costs were converted from Japanese yen to US dollars. Results: In patients who received HEC and needed APR, ICER with APR, relative to the non-APR regimen, was 4,884 USD per quality-adjusted life years (QALY) gained, which was far below the commonly accepted threshold of 50,000 USD/QALY gained. ICER was 20,911 USD/QALY gained in patients who received MEC and needed APR. In contrast, in patients who did not need APR and received HEC or MEC, ICER was 718,702 or 779,199 USD/QALY gained, respectively. Conclusions: Regardless of HEC or MEC, APR was cost effective for patients who truly need it. Results from our study warrant the development of accurate risk evaluation methods to determine the necessity of NK1RAs before initiating emetogenic chemotherapies.
The first screening experiences of breast cancer in northwest of Iran.
Authors: Roya Dolatkhah, Saeed Dastgiri, Gertruida H, de Bock, Zohreh Sanaat, Mahnaz Ranjkesh, Pooneh Jabbaripour, Shima Pashaee
Journal: Journal of Clinical Oncology (2018)

e13551 Background: Breast cancer is the most common cancer for women and the leading cause of cancer death among women worldwide. In Iran, it is the second common cancer and the seventh leading cause of cancer death for both sexes. The aim of this study is to improve breast cancer early detection using screening modalities in the northwest region of Iran. Methods: This is an ongoing feasibility trial started with 113 healthy women aged between 35 and 65 years selected randomly in the northwest of the country. After obtaining informed consent form, they are trained for breast self-examination. It has been planned to clinically follow up each woman for one year (with three-month intervals) followed by a mammography test at the end. At any part of the follow up, if any suspicious mass is found, the subject will be referred to oncologist for further medical interventions. Results: The mean age of the subjects was 46.9 (± 8. 8) years, with a mean Body Mass Index of 29.2 (±5.0). All women were trained for self-examination and underwent the clinical examinations. Eight women (so far) had suspicious mass in their clinical examinations. They have been referred to medical oncologist. Three of them were too referred to mammography with no malignant mass yet. Conclusions: According to the first part of this feasibility study, we have seen an improvement in knowledge and attitude of women about the importance of screening and early diagnosis of breast cancer in the region. However, some were fearfully concerned about screening procedures. Women with positive family history of breast cancer, and those with higher education level showed proper compliance.
P01.157 Glioma patients show reduced default mode deactivation during complex language production
Authors: J M Jansma, G Kaya, G J M Rutten
Journal: Neuro-Oncology (2018)

Language production is usually fast, precise and effortless. However, in some cases, for instance if we experience difficulty finding a word automatically, language production becomes a more difficult cognitive task. Functional MRI studies have shown that execution of a more difficult word search task such as the widely applied verb-generation task is associated with left lateralized activation of a fronto-temporal network (‘FTN’). It is however also associated with right lateralized inhibition of a network called the ‘default mode network’ (‘DMN’). The precise function of the DMN is still largely unknown, but recent studies have suggested that inhibition does facilitate cognitive task execution. In this study we examined a large set of clinical functional MRI scans measuring activation patterns associated with verb generation in patients with a low or high grade glioma. Results were also compared to those of healthy controls. We specifically looked at the level of activation in the FTN and DMN. This study used presurgical fMRI data of patients with a low-grade (‘LGG’: N= 96) or high grade glioma (‘HGG’: N = 110), as well as healthy controls (‘HC’: N = 16). FMRI scans were produced using a 3T Philips scanner (PRESTO pulse sequence, voxel-size: 4x4x4 mm, TE: 1.5 sec). Scans were corrected for movement and analysed. Individual activation maps were spatially normalized to MNI space. The average signal change during a covert verb generation task was calculated using cube-shaped ROIs (15mm3) over important regions of the FTN and DMN. Signal changes were averaged over all ROIs for each network. A multivariate analysis was performed to examine differences in network activation between the three groups. Follow-up univariate tests were performed for each group and network. Statistical analyses revealed a significant network by group interaction (F(2,219) = 5.70, p = 0.004). Follow-up analysis revealed that this interaction reflected less deactivation of the DMN in both LGG (F(1,110) = 4.43, p = 0.04) and HGG patients (F(1,124) = 8.00; p = 0.005) compared to HC. Activation in the FTN did not differ significantly between groups (LGG: F(1,110) = 0.006; p = 0.94; HGG(1,124): F = 0.20, p = 0.66). Patients with a glioma show less inhibition of the DMN during word search tasks then healthy subjects, independent of the grade of the glioma. It is hypothesized that inhibition of the DMN can facilitate cognitive task execution. Our results add new knowledge that may help in the understanding of deficits in language production as well as related cognitive tasks
DNA-based genomic profiling for classification of tissue of origin for patients with carcinoma of unknown primary site.
Authors: Lee A Albacker, Michael E Goldberg, Lukas C. Amler, Garrett Michael Frampton, Jeffrey S. Ross, James Suh, Vincent A. Miller, Phil Stephens, Juliann Chmielecki
Journal: Journal of Clinical Oncology (2016)

11519 Background: Carcinoma of unknown primary (CUP) has a poor prognosis and accounts for diagnoses in > 30,000 patients annually in the United States. Current tissue of origin (TOO) methods use protein or RNA-based expression signatures, are costly, and often provide little clinically relevant information. We previously showed that use of comprehensive genomic profiling (CGP) identifies a clinically relevant genomic alteration in 96% of CUPs. We hypothesized that CGP could also potentially identify a TOO for some CUP patients, further refining potential targeted therapeutic options. Methods: DNA alterations from 44,065 samples that underwent CGP as part of standard clinical care were classified using logistic regression based on mutational profiles and select clinical features. Results: We first trained a logistic regression classifier to identify non-small cell lung cancers (NSCLC) with alterations in EGFR, ERBB2, BRAF, MET, KRAS, ALK, RET, or ROS1 (lung gene set). In cross-validation, the classifier correctly identified 79% of NSCLCs (92% of EGFR mutant samples) and 93% of non-NSCLCs. When applied to a set of 1352 CUPs with an alteration in the lung gene set, 425 (31%) were predicted to be NSCLC. We next trained a classifier to distinguish BRAF V600-mutant colorectal cancers (CRCs) from other BRAF V600-mutant cancers. The classifier correctly identified 90% of CRCs and 93% of non-CRC. Use of this classifier with a BRAF-mutant CUP data set predicted 32/87 (37%) of BRAF-mutant CUP tumors to be CRC. Conclusions: In a large series of CUP patients with alterations in the lung gene set, one-third were likely NSCLC, and could potentially benefit from approved targeted therapies in this disease. When applied to BRAF V600-mutant CUPs, 37% were predicted to be CRC, and therefore single agent vemurafenib therapy is unlikely to be effective and combination therapy indicated. This approach is useful for identifying targeted therapeutics likely to be effective based on molecular match and TOO. We plan to extend this DNA-based tool to 4 additional tumor types. Application of this classifier to CUPs may help identify therapeutic strategies from CGP without the need for additional material or testing.
Towards mapping immune responses of nasopharyngeal carcinoma in Saudi Arabian patients, single institution experience.
Authors: Naser Al-Rajhi, Hussein Soudy, Shamayel Mohammed, Hatem Khoja, Hazem Ghebeh
Journal: Journal of Clinical Oncology (2017)

e17541 Background: The prevalence of Nasopharyngeal Carcinoma (NPC) is higher in Saudi Arabia compared to western countries. Genetic susceptibility and/or environmental factors (like infection with Epstein-Barr virus) contribute to the development of this tumor. There is a lack of information on the expression of markers related to the immune response in Saudi NPC patients. Methods: Here we report on profiling of two cohorts of NPC cases from patients treated at King Faisal specialist hospital &amp; Research cneter (KFSH&amp;RC) using the most relevant immune markers. The first cohort included 54 patients with local NPC while the other cohort included 25 cases of metastatic NPC at presentation. Immunostaining was done using Ventana benchmark fully automated system. Two anatomical pathologists (SM &amp; HK) scored the NPC cases for CD3+ infiltrating lymphocytes (TIL), and their sub-fractions co-staining for CD8, FOXP3 and/or PD-1. On the other hand, PDL1 expression was assessed on tumor cells. Statistical analysis was done using JUMP Pro 13 software. Results: There was an induction of membranous PDL1 expression on tumor cells of 70 and 64% in local and metastatic cases respectively. Interestingly, there was a significant number of cases with cytoplasmic expression of PDL1 (46% of local and 36% metastatic cases) in addition to the membranous expression. PD-1 was over-expressed (on ≥ 10% of TIL) in 52% and 68% of local and metastatic cases respectively. FOXP3+ T-cells were abundant in the tumor tissues as 78% of cases had ≥10% of their infiltrating CD3+ T-cells co-staining for nuclear FOXP3. Finally, CD8 were an abundant fraction of total CD3+ infiltrating T-cells in more than 60% and 78% of Local and metastatic cohorts respectively. Correlation of the above studied immune markers with patients clinical outcome shows statistically significant correlation (p = 0.008) between low CD3+ T-cell infiltration in tumor tissues at diagnosis and the relapse of the disease. Conclusions: PDL1 is upregulated, FOXP3+ T-regs are abundant, only the low intensity of CD3+ lymphocytes could predict for higher chances of relapse. These preliminary profiling data provide the basis for future immunotherapy trials for NPC in KFSH&amp;RC
Selinexor, a selective inhibitor of nuclear export (SINE), in patients with unresectable melanoma.
Authors: Kari Lynn Kendra, Ryan Watson, Gregory B Lesinski
Journal: Journal of Clinical Oncology (2017)

e21014 Background: Limited effective therapies exist for patients with melanoma after progression on immune- and targeted-therapies. Treatment with selinexor, a potent small molecule inhibitor of exportin-1 (CRM/XPO1), results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leads to growth arrest and apoptosis in vitro, in xenograft models (BRAF +/-), and Phase I solid tumor trial. (Yang et al PLOS One, 2014, Razak et al JCO, 2016). Methods: Objectives of this single institution trial were to determine: the safety in melanoma patients, the clinical benefit rate, and efficacy at the MTD as measured by PFS. Patients received prior immunotherapy and a BRAF inhibitor (mutation positive). Lead-in phase is completed. Median number of prior systemic therapies = 2 (2 – 4). Selinexor (50 mg/m 2 ) was orally administered twice weekly, with 2-3 days off between doses. Toxicities were evaluated every 28-days. Tumor biopsies were collected for correlative analysis. Results: As of Jan 2017, 7 patients (0/7 BRAF mutant) were enrolled. Drug related AEs: neutropenia (grade 4) (1/7 patients), hyponatremia (grade 3) (1/7 patients), thrombocytopenia (Grade 3) (3/7 patients), anemia (Grade 3) (1/7 patients), and thromboembolic events (Grade 3) (1/7 patients). There were no DLT’s. Four patients experienced stable disease (SD); one patient had a minor response, for a disease control rate (DCR) of 71% (5/7). Mean duration of response was 207 days (70 – 335). One patient, removed from therapy due to a CNS met, continued with stable systemic disease off therapy for 177 days. Another patient, taken off therapy due to a non-drug related adverse event, remained SD for 127 days. Conclusions: These preliminary results demonstrate that selinexor is well tolerated with supportive care, is safe for melanoma patients dosed at the 50 mg/m 2, and has the potential to control disease progression as a single agent in patients with prior BRAF inhibitor and immunotherapy. Patients are currently enrolling at a flat 60 mg dose. Correlative studies including evaluation of selinexor target engagement and exploratory markers of drug response are underway. Clinical trial information: NCT02120222. Clinical trial information: NCT02120222.
Tumor burden (TB) and treatment exposure (TE) in patients (pts) with malignant pleural mesothelioma (MPM) receiving nintedanib (N)/placebo (P) in combination with first-line pemetrexed/cisplatin (PEM/CIS) in phase II of the LUME-Meso study.
Authors: Sanjay Popat, Federica Grosso, Nicola Steele, Anna K. Nowak, Silvia Novello, Laurent Greillier, Martin Reck, Tom John, Paul Taylor, Natasha B. Leighl, Giovanni Luca Ceresoli, Jens Benn Sørensen, Nick Pavlakis, David Planchard, Brett Gordon Maxwell Hughes, Julien Mazieres, Mark A. Socinski, Hannes Buchner, Jose Barrueco, Giorgio V. Scagliotti
Journal: Journal of Clinical Oncology (2018)

8566 Background: In the double-blind, placebo-controlled phase II/III LUME-Meso trial, N was combined with up to 6 cycles of PEM/CIS, followed by N monotherapy until progression or toxicity. The primary analysis of phase II showed improved progression-free survival (primary endpoint) with N vs P (hazard ratio (HR) = 0.56; 95% confidence interval (CI): 0.34–0.91; p = 0.017); for overall survival HR = 0.77; 95% CI 0.46–1.29. We evaluated outcomes in the combination and monotherapy phases to understand better the overall study results. Methods: Pts with unresectable MPM (ECOG PS 0–1), stratified by histology, were randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P; 200 mg bid, Days 2–21), followed by N or P monotherapy maintenance. TE was analyzed for PEM/CIS, N and P. TB, measured using sum of diameter by modified RECIST 1.0, was analyzed over time, using a mixed-effects model in pts with at least two imaging datapoints. Results: 87 pts were randomized: 85 pts (N: 44, P: 41) were treated; 61 pts (N: 34, P: 27) received maintenance; median follow-up was 29 months. Both groups received a median of 6 cycles of PEM/CIS. In the combination phase, greater and longer reduction in TB was seen with N. Average TB reduction from baseline to nadir was 46% greater for N vs P (33.1 vs 22.6 mm). The nadir occurred at 4.1 vs 2.3 months for N vs P. In the monotherapy phase, treatment with N vs P showed markedly slower tumor regrowth from nadir (e.g. +46% vs +112% at 12 months). Median TE (N vs P) was 7.8 vs 5.3 months over the full treatment period. In the monotherapy phase, TE was 5.3 vs 2.8 months. The proportion of pts with serious AEs (N vs P) was similar between treatment groups during combination (34% vs 32%); during monotherapy the rate was 15% vs 26%. Conclusions: Pts receiving N had greater, more sustained reduction in TB than those receiving P and remained on active therapy for longer. AEs were manageable in both phases of the trial. Together with the primary study results, these analyses show that combination of N + PEM/CIS followed by N maintenance delivers clinical benefit to pts with MPM. Clinical trial information: NCT01907100.