bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I dose expansion cohort study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509).
Authors: Osei-Tutu Akosua , Nunes Ana Tablante , Lee Jung-min , Yu Minshu , Hernandez Lidia , Chen Helen X. , Takebe Naoko , Houston Nicole D. , Ekwede Irene , Steinberg Seth M. , Chen Jin-Qiu , Cao Liang , Figg W. Douglas , Butcher Donna , Annunziata Christina M. , Kohn Elise C. 
Published: September 2018

2585 Background: Dasatinib is a known inhibitor of the SRC family kinases and is approved for use in chronic myelogenous leukemia. Bevacizumab inhibits angiogenesis, binding to human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity. VEGF receptor signals intracellularly via a cascade regulated by SRC. Given the presence of this signaling pathway in both tumor cells and endothelial cells, we hypothesized that attenuation of both SRC and VEGF simultaneously would have synergistic antitumor activity. We previously reported the maximum tolerated dose (MTD) of dasatinib 100mg daily with bevacizumab 10mg/kg q2wk in patients with advanced solid tumors. We now report clinical activity of the combination, and translational endpoints of an expansion cohort. Methods: This is a phase 1 dose escalation with non-randomized expansion cohort. We monitored safety, and response was assessed every 8 weeks using RECIST criteria. Correlative endpoints include blood flow by dynamic MR imaging, endothelial cell density by CD31 immunohistochemistry, functional angiogenic potential by plasma cytokines and rat aortic ring assay, and tumor cell activation state by phosphoprotein analysis. Results: We enrolled 39 patients at the MTD for a total of 50 patients on study, including both the dose escalation and dose expansion phases. No patient experienced dose limiting toxicities during dose escalation. The most common adverse events were grade 2 hypertension and proteinuria. By RECIST, 5 (10%) patients had a partial response, and stable disease was seen in 29 (58%) of patients with a range from 12-145+ weeks on study. We had two exceptional responders with endometrial carcinoma who continue on study to date (112 weeks and 145 weeks). Translational endpoints were correlated with clinical outcome. Conclusions: Bevacizumab and dasatinib are safe in combination, with potential clinical activity. This combination warrants further investigation in solid tumors. Ongoing translational research using specimens from exceptional responders will suggest potential biomarkers of clinical benefit, to be tested in future prospective clinical trials. Clinical trial information: NCT01445509.
SWI/SNF complex subunit aberrations in diverse cancers: Next-generation sequencing of 539 patients.
Authors: Groisberg Roman , Hong David S. , Janku Filip , Jiang Yunfang , Wei ChongJuan , Karp Daniel D. , Tsimberidou Apostolia Maria , Naing Aung , Bhalla Kapil N. , Meric-Bernstam Funda , Subbiah Vivek 
Published: September 2018

2588 Background: The SWI/SNF complex is an ATP-dependent chromatin remodeler that is enriched at promoters and enhancers of active genes. It has been implicated as both an oncogene and tumor suppressor. Specific subunit mutations have even been associated with specific cancers with increased PRC2 component EZH2 activity. EZH2/ EED inhibitors are in early stage development to target SWI/SNF complex. Methods: We analyzed 539 consecutive patients with diverse malignancies who were referred for Phase 1 clinical trials and had CLIA certified targeted next-generation sequencing (Foundation one) for presence of aberrations in SWI/SNF complex genes (ARID1A, ARID2, PBRM1, SMARCA4, SMARCB1). Patient charts were reviewed for general demographics (sex, age at diagnosis and death, performance status), tumor histology, stage, metastatic sites, treatment history, outcomes and co-occurring alterations. Results: Fifty patients had mutations in SWI/SNF subunits. Median age at diagnosis was 56 (14-79 years) and M:F ratio 21:29. Kidney, colorectal, ovary and breast were the most common among 15 different cancers. Most were stage IV at diagnosis (68%), had a strong family history of cancer (80%) & were smokers (42%). The most common mutated subunit was ARID1A (50%) followed by PBRM1 (16%), ARID2 (12%), SMARCA4 (12%), and SMARCB1 (10%). All mutations were predicted to be inactivating. Actionable co-occurring pathway alterations were found in 58% of patients, most commonly PI3K (26%), FGFR(16%), and NOTCH1/2 (10%). The majority of patients (62%) were enrolled on a clinical trial. Best responses on other targeted agents included 1 CR (BRAFV600E colon), 4 PR (transformed teratoma, skin SCC, ovarian, NSCLC), 12 SD. Exceptional responders included BRAFV600E colon cancer on BRAFi based therapy for 66 cycles, NSCLC on Nivolumab for 34 cycles, and MSI-H colon cancer on regorafenib/cetuximab for 27 cycles. Conclusions: The role of SWI/SNF in patients with extended clinical benefit from other targeted agents should be explored. Co-occurring genetic alterations are observed in PI3K, FGFR, and NOTCH pathways. Future pre-clinical and/or clinical studies could target these pathways in combination with EZH2/EED inhibitors.
The effect of supplemental estrogen on the outcomes of NSCLC patients in the SEER-Medicare database.
Authors: Heilbroner Samuel P. , Xanthopoulos Eric , Wang Tony J. C. , Cheng Simon 
Published: September 2018

2590 Background: Women with lung cancer have better survival regardless of treatment type. Estrogen has been shown to have cancer-specific and non-cancer effects. However, there is conflicting data on the effect of estrogen hormone therapy on lung cancer incidence and mortality in women. We used the SEER-Medicare database to examine the association of estrogen use with overall and cancer cause specific survival in elderly women with non-small cell lung cancer (NSCLC). Methods: Patients in our cohort were women 65+ years old; were diagnosed with Stage I-IV NSCLC between 2007 and 2012; had Part A and B coverage one year before to one year after diagnosis without supplemental coverage from a HMO; had Part D coverage during the 6 months prior to diagnosis; were not in a nursing home at diagnosis. Using an intention to treat analysis, drug use was defined as having at least one Part D claim for estrogen within six months prior to diagnosis. Event free survival was assessed using a multivariate Cox proportional hazard model accounting for the patient (age, socioeconomic status, race, Charlson score) and tumor (stage, site, histology) characteristics. Results: There were 10,562 patients in our cohort. 688 used estrogen and 9,874 did not. The median age was 75 years with median overall survival of 1.0 year. There was a significant difference in age, socioeconomic status, race, Charlson score, stage, site, and tumor histology between the two groups (p < 0.05 for all). Estrogen use was associated with a significant improvement in overall and cause specific survival on univariate and multivariate regression (see table). Conclusions: Estrogen was associated with a significant improvement in survival. Limitations of this study are inherent to a retrospective claims-based database without knowledge of actual drug use or intent. [Table: see text]
Epacadostat plus nivolumab in patients with advanced solid tumors: Preliminary phase I/II results of ECHO-204.
Authors: Perez Raymond P. , Riese Matthew John , Lewis Karl D. , Saleh Mansoor N. , Daud Adil , Berlin Jordan , Lee James J. , Mukhopadhyay Sutapa , Zhou Li , Serbest Gul , Hamid Omid 
Published: September 2018

3003 Background: ECHO-204 is an ongoing, open-label, phase 1/2 (P1/2) study of epacadostat (E; potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (NSCLC, MEL, OVC, CRC, SCCHN, B-cell NHL [including DLBCL], GBM). Preliminary P1/2 safety and tolerability outcomes for the overall study population and P2 response for select tumor types (SCCHN, MEL, OVC, CRC) are reported. Methods: In P1 dose escalation, pts received E (25, 50, 100, 300 mg BID) + N (3 mg/kg Q2W); in P2 cohort expansion, pts received E (100 or 300 mg BID) + N (240 mg Q2W). Safety/tolerability was assessed in pts receiving ≥1 E + N dose. Response was assessed in RECIST v1.1 evaluable pts; for recently enrolled pt subgroups, only preliminary DCR (CR+PR+SD) is presented. Results: As of 29OCT2016,241 pts (P1, n = 36; P2, n = 205) were enrolled. No DLT was observed in P1. Most common TRAEs (≥15%) in pts treated with E 100 mg (n = 70) and E 300 mg (n = 135) were rash (33% and 22%, respectively), fatigue (26% and 31%), and nausea (24% and 19%). Rash was the most common grade ≥3 TRAE in E 100 mg and E 300 mg subgroups (10% and 12%). TRAEs led to discontinuation in 7% (E 100 mg) and 13% (E 300 mg) of pts. There were no TR-deaths. For the 23 recently enrolled, efficacy-evaluable SCCHN pts treated with E 300 mg, preliminary DCR was 70% (n = 16). Of 30 MEL pts, 8 were treated with E 100 mg and 22 were more recently enrolled and treated with E 300 mg. ORR (CR+PR) and DCR in MEL pts treated with E 100 mg were 75% (n = 6; all PR) and 100% (n = 8; 2 SD), respectively. Preliminary DCR in MEL pts treated with E 300 mg was 64% (n = 14). Of 29 OVC pts, 18 were treated with E 100 mg and 11 with E 300 mg.ORR and DCR for OVC pts treated with E 100 mg were 11% (n = 2; 2 PR) and 28% (n = 5; 3 SD); for 11 OVC pts treated with E 300 mg, ORR and DCR were 18% (n = 2; 2 PR) and 36% (n = 4; 2 SD).For 25 CRC pts (all E 100 mg), ORR and DCR were 4% (n = 1; PR) and 24% (n = 6; 5 SD).Safety/efficacy evaluations are ongoing for all cohorts. Conclusions: E + N was generally well tolerated up to the maximum E 300-mg dose. P2 ORR/DCR outcomes are promising, particularly in SCCHN and MEL pts. Updated data will be presented at the meeting. Clinical trial information: NCT02327078.
Biomarkers associated with neurotoxicity in adult patients with relapsed or refractory B-ALL (R/R B-ALL) treated with CD19 CAR T cells.
Authors: Santomasso Bianca , Park Jae Hong , Riviere Isabelle , Mead Elena , Halton Elizabeth , Diamonte Claudia , Purdon Terence , Senechal Brigitte , Li Daniel , Sadelain Michel , Brentjens Renier J. 
Published: September 2018

3019 Background: CD19-specific chimeric antigen receptor (CAR) modified T cells produce high and durable anti-tumor activity, but can be associated with treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity (NTX). NTX is poorly understood and it hasn't been clear where to focus further research. We report cerebrospinal fluid (CSF) data and neuroimaging characteristics of patients (pts) who developed severe NTX (sNTX) during our phase I clinical trial of CD19-specific 19-28z CAR T cells for adult pts with R/R B-ALL, which suggest new avenues for future research. Methods: 51 adult pts with R/R B-ALL were treated with 19-28z CAR T cells following conditioning chemotherapy at MSKCC. We analyzed the incidence and grade of NTX, CRS and correlative biomarkers in blood and CSF. Results: 21/51 treated pts developed sNTX (grade ≥3) complications such as encephalopathy, aphasia, depressed level of consciousness, myoclonus, and seizure. No pt developed grade 5 NTX and, in all but one case, neurologic symptoms fully resolved. We collected CSF by lumbar puncture and blood from 14 pts at the time of peak NTX. sNTX was correlated with pre-infusion disease burden (p = 0.013) and peak CAR T cell expansion in the blood (p = 0.0001), but we found no significant correlation between NTX grade and the CAR T cell concentration in the CSF during NTX. Instead CSF protein level was correlated with neurotoxicity grade (p = 0.0109). The cytokines IL6, IL8, IL10, IFNγ and GCSF were elevated in CSF over serum at the time of NTX and correlated with CSF protein levels (all p < 0.005). These were distinct from serum cytokines significantly associated with sNTX at d3 of T cell infusion: GMCSF, IFNγ, IL15, IL5, IL10, and IL2 (all p < 0.01). 4/21 patients developed a pattern of reversible MRI T2/FLAIR hyperintensity involving the bilateral thalami, dorsal pons, and medulla. Conclusions: NTX is predominantly reversible. MRI findings suggesting transient toxicity to deep grey structures and findings of a CSF-specific cytokine profile expand the hypotheses on the mechanism of NTX. Future studies will focus on determining the etiology of the CSF protein elevation and the distinct cytokine profile. Clinical trial information: NCT01044069.
Cytokine release syndrome (CRS) and neurotoxicity (NT) after CD19-specific chimeric antigen receptor- (CAR-) modified T cells.
Authors: Turtle Cameron John , Hay Kevin Anthony , Gust Juliane , Hanafi Laila-Aicha , Li Daniel , Liles W. Conrad , Wurfel Mark , Harju-Baker Susanna , Myerson David , Gonzalez-Cuyar Luis , Yeung Cecilia CS , Riddell Stanley R. , Maloney David G. 
Published: September 2018

3020 Background: CD19 CAR-T cells have produced impressive responses in CD19+ ALL, NHL and CLL. Detailed understanding of the presentation and pathogenesis of CRS and NT will facilitate safe CAR-T cell use in multicenter trials. Methods: We treated 161 adults with B-ALL, NHL or CLL with anti-CD19 CAR-T cells, formulated in a 1:1 CD4/CD8 ratio and infused after lymphodepletion chemotherapy in a dose finding study (NCT 01865617) to identify a MTD in each disease. Results: 133 patients (pts) completed toxicity assessment. CRS developed in 71% (60% gr 1-2, 4% gr 3, 8% gr ≥4). Fever was the first sign of CRS and preceded organ toxicity, allowing safe outpatient administration of CAR-T cells. NT was observed in 40% (19% gr 1-2, 16% gr 3, 5% gr ≥4) and gr ≥3 NT presented a median of 4.5 days after CRS onset. The time from onset to peak of NT was 2 days. CRS and NT were reversible with the exception of 6 pts who died, 4 during the dose-finding phase of the study. In multivariable analyses, higher CAR-T cell dose and malignant B cells in marrow (BM) were associated with CRS; and CAR-T cell dose, malignant BM B cells, more intensive lymphodepletion, and prior neurologic comorbidities were associated with NT. Probability curves of response, CRS and NT in relation to blood CAR-T cell counts show that toxicity mitigation by CAR-T cell dose reduction may be feasible in B-ALL without impairing BM response; however, dose reduction may reduce nodal response in NHL and CLL. Analysis of clinical parameters revealed that pts who later developed severe CRS or NT could be identified early after CAR-T cell infusion by higher fever, greater vascular instability, and more severe hypoalbuminemia. Paired serum-CSF studies and autopsy data suggest blood-brain barrier disruption in severe NT. High serum IL-6, IL-15, MCP-1 and IL-10, and endothelial activation markers on day 1 after infusion correlated with subsequent toxicity, which identifies pts for early intervention to prevent severe toxicity. Conclusions: CAR-T cells can be safely administered in the outpatient setting. Clinical and laboratory biomarkers allow early identification of a small subset of pts who might develop serious toxicity, facilitating study of preventive strategies. Clinical trial information: NCT 01865617.
Maintenance immunotherapy in stage IV cancer patients who have a clinical benefit from chemotherapy.
Authors: Recchia Francesco , Candeloro Giampiero , Rea Silvio 
Published: September 2018

3021 Background: Even if patients with stage IV cancer (AC) may have prolonged remissions with chemotherapy (CT), the majority of them, will eventually relapse. In vitro studies suggest that natural killer (NK) cells mediate lytic activity against cancer cell lines and that high expression of vascular endothelial growth factor (VEGF) promotes tumor progression through neoangiogenesis. We have shown that low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) increased NK cells and decreased VEGF, in patients with AC and a clinical benefit on CT (Clin Cancer Res 7: 1251, 2001). We hypothesized that IL-2 and RA, increasing NK and decreasing VEGF, could improve disease-free survival (DFS) and overall survival (OS) in a minimal residual disease setting. Primary endpoint was the evaluation of NK cells and VEGF; secondary endpoints were DFS, OS and toxicity. Methods: 500 patients with AC, and a clinical benefit from CT, were given subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg, 5 days/week, 3 weeks/month, until progression. NK cells, VEGF, response and toxicity were assessed every 4 months. Results: After a median follow-up of 112 months (range 63-200), a total of 4400 courses of CT and 2634 courses of immunotherapy were delivered. A statistically significant improvement of NK cells [from a mean of 309 ± 76/mm3 to a mean of 579 ± 74/mm3 (p < 0.001)] and a decrease of VEGF [from a mean of 520 ± 75 pg/mm3 to a mean of 150 ± 12 pg/mm3, (p < 0.001)], were observed. Eighteen-years DFS and OS were 29% and 32%, respectively. A significant improvement, with respect to NCI SEER data (*), was observed in the 5-year OS rate for the most common treated AC: Breast cancer 55% vs. 6% *; Lung cancer 22% vs. 4.3% *; Colorectal cancer 43.5% vs. 21%*. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: Our data show that immunotherapy with IL-2/RA, may determine, with an acceptable toxicity profile, a statistically significant improvement of NK cells, a decrease of VEGF, and better 5-year survival rates with respect to NCI SEER data, for all major stage IV cancers.
Response to first-line chemotherapy regimen to predict efficacy of nivolumab in lung cancer.
Authors: Kaderbhai Coureche Guillaume , Richard Corentin , Fumet Jean david , Aarnink Anne , Ortiz-Cuaran Sandra , Perol Maurice , Foucher Pascal , Coudert Bruno P. , Favier Laure , Lagrange Aurelie , Limagne Emeric , Hofman Paul , Saintigny Pierre , Ghiringhelli Francois 
Published: September 2018

3026 Background: Nivolumab is a monoclonal antibody, targeting PD-1 receptor and demonstrating durable clinical benefit in 20% of metastatic NSCLC patients in second and further treatment lines. The expression of one of the PD-1 ligand, PD-L1 assessed by IHC is associated with better outcome. However, robust predictive markers of efficacy are lacking. Methods: 115 pts with stage IV NSCLC (42 squamous, 73 adenocarcinoma) were included in this retrospective study in 4 different institutions. They received nivolumab (3 mg/kg IV Q2W) after at least one line of systemic platinum-based chemotherapy. Response to first line chemotherapy and to nivolumab (RECIST 1.1) was determined on CT scan by two physicians. Association between best response to first-line regimen and PFS, OS or response to nivolumab was determined using both Chi2 and Cox analysis. Results: 46 (40%), 44 (38%) and 25 (22%) patients experimented PR, SD and PD to first-line platinum-based chemotherapy. 25 (22%), 34 (29.5%), 56 (48.5%) experimented PR, SD and PD to nivolumab. 59.5% (53/89) of patients who experimented clinical benefit (SD+PR) to first-line also experimented clinical benefit to nivolumab while only 20% (5/25) of patients with PD as best response to chemotherapy experimented clinical benefit to nivolumab (Chi2 test p = 0.002). The type of first-line doublet chemotherapy did not influence the response rate to nivolumab. Cox uni and multivariate models included age, histology and performance status underlined that patients with clinical benefit from chemotherapy had improved PFS with nivolumab (P = 0.002) (median PFS on nivolumab regimen of 4.9, 3.3 and 1.8 months for patients with PR, SD and PD to first-line, respectively). Similar results were obtained for OS (P = 0.03). Conclusions: Our data suggest that response to first-line chemotherapy may be a good surrogate marker of response, PFS and OS to post-platinum nivolumab in metastatic NSCLC.
Germ-line biomarkers disrupting microRNA regulatory pathways to predict toxicity and response to anti-PD-1 and anti-PD-L1 therapies.
Authors: Weidhaas Joanne B. , Telesca Donatello , Kalbasi Anusha , Salzman David , Ribas Antoni 
Published: September 2018

3040 Background: Identifying responders to developing immune therapies is of high priority, yet identifying patients who will suffer from toxicity, which represents a unique spectrum of side effects, termed immune-related adverse events (irAEs), is critical. The complex host-specific response to immune therapies led us to hypothesize that germ-line mutations, present in both the tumor and in the host’s immune system, may be a source of biomarkers. As there is compelling evidence that recently discovered germ-line mutations disrupting microRNA (miRNA) networks act as biomarkers of treatment response and baseline immune status, we evaluated such mutations in patients treated with these therapies. Methods: Patients treated with anti-PD1 or anti-PDL1 therapy alone and clinically documented response and toxicity were tested with a panel of over 150 vetted germ-line miRNA based biomarkers. Of 85 patients evaluated for response, 75 had melanoma, and 10 had NSCLC. For analysis of toxicity, an additional 4 patients with other cancer types were included. Subjects were classified as responders (Complete, Partial) versus non-responders (Progressive, Stable), or as experiencing low irAEs (grade 0 and 1) versus high irAEs (grade 2 and above). We used Chi-squared analysis for base evaluation and then compared three classification techniques including classification trees, random forests and Bayesian probit regression with non-local priors. We estimated classification performance via leave-one-out cross validation. Results: By Chi-Squared analysis we found over a dozen biomarkers associated with response, and a dozen biomarkers associated with toxicity. These included germ-line mutations in 3’ untranslated regions as well as in miRNA promoter regions. We found that both classification trees and Bayesian probit compared reasonably well with random forests. We found a response signature with a specificity of 89% by Random Forests, and a toxicity signature with a specificity of 76% by Random Forests. Conclusions: We have shown that a new class of germ-line mutations disrupting miRNA regulatory networks can act as biomarkers of response and toxicity to anti-PD1 and anti-PDL1 therapy.