tbuckley/cabot-search huggingface dataset:
A phase II trial of the aurora kinase A inhibitor MLN8237 in patients with metastatic castrate resistant and neuroendocrine prostate cancer.
Authors: Himisha Beltran, Mark A. Rubin, Juan Miguel Mosquera, Paul J. Christos, Olivera Calukovic, Irene Karpenko, Jacek K. Pinski, Daniel Costin Danila, David M. Nanus, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2013)

TPS5096 Background: NEPC can rarely arise de novo but more commonly arises as a mechanism of resistance in the setting of advanced prostate cancer. Transformation to NEPC is likely promoted by potent hormonal therapies and is currently under-recognized. There is no effective therapy for NEPC and most patients (pts) survive less than one year. We have found that Aurora kinase A (AURKA) and N-myc (MYCN) are significantly overexpressed and amplified in NEPC compared to prostate adenocarcinoma, and cooperate to induce neuroendocrine (NE) differentiation in prostate cancer (Beltran et al, Cancer Disc 2011). In preclinical models, aurora kinase inhibition results in dramatic and preferential anti-tumor activity in NEPC. Methods: In this single arm, multi-institutional Phase II trial, pts with metastatic prostate cancer need to meet at least one NEPC entry criterion: 1) histologic diagnosis of small cell or NEPC, 2) &gt;50% immunohistochemical staining for NE markers, 3) development of liver metastases in absence of PSA progression, or 4) serum chromogranin &gt;5x normal or neuron specific enolase &gt;2x normal. Study will be open at 10 institutions including PCCTC sites. After a mandatory on-study research biopsy, pts will be treated with MLN8237, an orally administered Aurora kinase A inhibitor at 50 mg twice daily for 7 days repeated every 21 days. The primary endpoint is objective response rate (ORR). Secondary endpoints include overall survival, progression free survival, PSA response rate, circulating tumor cell response, and serum NE marker response to therapy. A number of correlative studies including AURKA, MYCN, AR, and exome and RNAseq are embedded in this trial in order to molecularly define this aggressive and poorly characterized disease. A Simon 2-stage design will be employed with up to 60 subjects providing 80% power to determine if the true ORR is &gt;30% and 95% power if the true ORR is &lt;15%, assuming a 5% level of significance. A subset of at least 20% meeting histologic entry criteria is embedded.
Defining the spectrum and "overlap" of HER2 aberrations in lung cancers: Associations of HER2 protein overexpression, <i>HER2</i> amplification, and <i>HER2</i> mutation.
Authors: Bob T. Li, Dara S. Ross, Jamie E. Chaft, Meier Hsu, Severine Kako, Dara L. Aisner, Mark G. Kris, Marileila Varella-Garcia, Maria E. Arcila
Journal: Journal of Clinical Oncology (2015)

8067 Background: Human epidermal growth factor receptor 2 (HER2, ERBB2) aberrations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 protein overexpression, HER2 gene amplification and HER2mutation in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering and the University of Colorado combined their data on HER2 in lung cancers. Methods: Tumor specimens from 175 patients with lung adenocarcinomas with no prior targeted therapy were evaluated for the presence of HER2 overexpression, HER2 amplification and mutation. Overexpression was assessed by immunohistochemistry (IHC) using the 4B5 Ventana antibody. Amplification was assessed by fluorescence in-situ hybridization (FISH) using FDA approved probe sets (PathVysion, Abbott and HER2 IQFISH pharmDx, Dako) and defined as HER2/CEP17 ratio ≥ 2.0. Mutation was assessed by fragment analysis and mass spectrometry genotyping for indels and recurrent point mutations in exon 20, respectively. The frequencies of HER2 overexpression, HER2 amplification and mutation were calculated and their concordance examined. Results: HER2 amplification by FISH was detected in 5 of 175 (3%) cases, and 46 (26%) showed polysomy (HER2 copy ≥ 4 but HER2/CEP17 ratio < 2). HER2 overexpression (2+, 3+) on IHC was not detected in the 25 specimens tested to date and negative IHC correlated with negative results on FISH. HER2 mutation was detected in 4 of 145 (3%) specimens, including 3 identical 12bp insertions [(p.A775_G776insYVMA (c.2324_2325ins12)] and a 9bp insertion, all in exon 20. None of the HER2 mutant cases were amplified and 3 had polysomy. Conclusions: HER2 mutations are not associated with HER2 amplification or HER2 protein overexpression suggesting a distinct entity and therapeutic target. “HER2-positive lung cancers” may not be an adequate term and patient cohorts for the study of HER2 targeted agents should be defined by the specific HER2 aberrations present. Funded in part by Boehringer-Ingelheim, NCI 1 RC2 CA148394-01, NCI P50CA058187, and NCI CCSG P30CA046934.
Demographic and insurance-based disparities in diagnosis of stage IV cervical cancer: A population-based analysis using NCDB.
Authors: Mary Funke, Gaurav Goyal, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2015)

e17589 Background: The stage of cervical cancer strongly influences the prognosis. This is the largest epidemiological study to examine the demographic and insurance characteristics of patients diagnosed with stage IV cervical cancer. Methods: It is a retrospective study of patients diagnosed with cervical cancer from 2000 to 2012 using the National Cancer Database (NCDB). The NCDB consists of approximately 70% of all newly diagnosed cancers in the United States. There were 131,320 women diagnosed with cervical cancer. Chi square test was used to test significance. Results: From 2000 to 2012, 11.2% (14,744) of patients were diagnosed with stage IV cervical cancer. Although the incidence of cervical cancer has increased minimally since 2000, the proportion of stage IV has increased from 9.9% to 12.4%. Groups that have a decreased incidence of presenting with stage IV cancer included: Private insurance (8.4%); Hispanics (9.2%) and age less than 50 (7.2 %). Groups with an increased chance of presenting with stage IV include Medicare (16.2%); uninsured (13.5%); over age 50 (15.7 %); blacks (13%); and distance to cancer center less than 5 miles (13%) (Table 1). Lower education level and household income are associated with a minimal increase in stage IV cancer diagnosis. Conclusions: This study emphasizes the factors associated with diagnosis of Stage IV cervical cancer. It highlights a decreased incidence in Hispanics, age less than 50, and those with private insurance. At risk groups included older, uninsured, and black population. Epidemiology of stage IV cervical patients. Stage IV (%) Year of Diagnosis* 2000-2012 11.2 2000-2006 9.9 2006-2012 12.4 Insurance* Private 8.4 Medicaid 12.6 None 13.5 Medicare 16.2 Age* 20-29 3.9 <20 4.7 30-39 5.6 40-49 9.2 50-59 14.5 60-69 16.2 70-79 16.7 90+ 17.1 80-89 17.3 Race/ethnicity * Hispanic 9.1 White 11.3 Black 13.2 Distance traveled (miles)* >100 9.5 50 to 99 9.9 25 to 49 10.1 10 to 24 11.1 5 to 9 11.9 <5 13.2 Education* % without a HS degree <6 10.4 2012 census 6-10.9 10.7 11-14.9 11.3 >23 11.4 15-22.9 11.8 Household income (USD)* >69,000 10.2 2012 census per year 44,000-52,999 11 53,000-68,999 11.1 36,000-43,999 11.5 *P –value<.0001 <36,000 10.2
Development of the molecular diagnostic (MDx) DLBCL Lymphoma Subtyping Test (LST) on the nCounter Analysis System.
Authors: Brett Wallden, Sean Ferree, Harini Ravi, Naeem Dowidar, Tressa Hood, Patrick Danaher, Afshin Mashadi-Hossein, George Wright, Carl Schaper, James Justin Storhoff
Journal: Journal of Clinical Oncology (2015)

8536 Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin's lymphoma with two distinct molecular cell-of-origin (COO) subtypes known as germinal center B-cell (GCB) or activated B-cell (ABC). DLBCL subtypes have been reported to be prognostic and potentially predictive of treatment benefit, underscoring the need for a precise and accurate MDx test. NanoString's LST is based on the Lymph2Cx gene expression profile (GEP). These studies describe the development of the LST and analytical robustness and clinical accuracy of the Linear Predictor Score (LPS) and DLBCL subtypes (ABC and GCB). Methods: 51 banked formalin fixed, paraffin embedded (FFPE) DLBCL specimens were used to recalibrate the algorithm using a clinical grade assay. The subtype accuracy of the final locked algorithm was verified by testing 68 independent specimens with gold standard (GS) GEP results. Analytical precision was measured across 2 operators and 3 reagent lots by testing 10 FFPE DLBCL RNA samples. Reproducibility was measured across 2 operators and pathologists by testing replicate tissue sections from 64 FFPE DLBCL blocks following independent pathology review of H&E slides. Following guided macrodissection of pathologist identified tumor tissue, isolated RNA was tested on the NanoString nCounter system. The assay was evaluated across the assay RNA input range (62.5-1000 ng) and with the inclusion of adjacent non-tumor tissue. Results: The estimated misclassification rate compared to the GS result was 5.9% (95% CI: 4.6%-7.1%). The total standard deviation in LPS was < 2% of the score range, including all sources of assay variation, with no significant differences between operators or reagent lots. Average LST subtype concordance with independent pathology review was > 95% with no GCB to ABC misclassifications (or vice versa). The assay was robust across the specified range and against the inclusion of tissue interferents. Conclusions: The NanoString LST is a highly precise and accurate method for determining the COO from FFPE DLBCL tissue. The assay is well suited to clinical applications and is being used to select ABC patients for a Phase III study investigating lenalidomide (REVLIMID) in DLBCL.
Effect of cancer-associated fibroblasts on cell proliferation and resistance to EGFR-TKI in direct coculture with lung cancer cell lines.
Authors: Jinseon Lee, So-Jung Choi, Jhingook Kim, Sung-Hyun Kim
Journal: Journal of Clinical Oncology (2012)

e18083 Background: Identical lung cancer cells may get diversified depending on tumor microenvironments. We hypothesized that diversity of cancer associated fibroblasts renders identical lung cancer cells various tumor characteristics such as drug responsiveness and proliferation rate. To test this hypothesis, we isolated cancer associated fibroblasts from 20 different lung cancers, and compared their effects on the proliferation and drug responsiveness of lung cell lines. Methods: Cancer associated fibroblasts were isolated from 20 solid tumors of NSCLCs, and treated with Mitomycin to control the overgrowth during cocultures. H358 and A549 cells were mixed with cancer associated fibroblasts in 1:1 ratio and co-cultured for 4-7 days. Cell number was scored by time-lapse photography, and cell morphology was observed under fluorescent microscope. Expression of cell type markers were examined. Responsiveness to Erlotinib was examined in coculture condistions. Results: Cancer associated fibroblasts stimulated cancer cell proliferation ranging from almost no effects to approximately 3 folds. Coculture in transwell with no direct contacts with cancer cells showed minimal stimulatory effects. Direct contacts induced dramatic changes in cancer cell morphology from cohesive epithelial colonies to dispersed fibroblastic single cells. EMT markers such as down-regulation of Cytokeratins and up-regulation of Vimentin were detected in GFP positive cells. A549 cells that were sensitive to 15 uM Erlotinib (IC50=7.5uM) became resistant when co-cultured with cancer associated fibroblasts. Conclusions: In this study, cancer associated fibroblasts isolated from different lung cancers induced significant changes in tumor cell characteristics such as proliferation, EMT, and drug responsiveness.
A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1–7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML)
Authors: N. Vey, J. Bourhis, H. Dombret, D. Bordessoule, T. Prebet, A. Charbonnier, P. Squiban, B. Damholt, D. Blaise, D. Olive
Journal: Journal of Clinical Oncology (2009)

3015 Background: The outcome of the majority of patients with AML remains poor, especially in the oldest patients. Allogeneic SCT is a curative approach for AML. In some models, it has been shown that KIR mismatch is important for the anti-leukemic effect of the graft, most probably through unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts. To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated. We present the results of the first-in-human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60–80 years with non promyelocytic AML in first CR following induction and 1–6 cycles of consolidation chemotherapy, normal renal, and hepatic functions, KIR-expression on patient NK-cells and who signed informed consent were eligible.Dose escalation (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg) was studied using a 3+3 scheme. Pharmacokinetic (PK) and circulating cytokines (MIP1β, TNF) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: To date, inclusion has been completed until 1mg/kg cohort. Data of the first 15 patients (end of 0.3 mg/kg cohort) are available. No dose limiting toxicity has been observed. Side effects that could be related to drug administration were mild and transient. The first dose level resulted in a transient KIR occupancy ranging from 20 to 50%. PK values were then in line with modelling data, resulting at 0.3 mg/kg in a Cmax= 6350 ± 504 ng/mL, &gt;80% KIR saturation for one week, and desaturation in the following week. As expected for an IgG4, NK cell numbers were unaffected by the treatment. Upregulation of CD69 on NK cells and concomitant increases in TNF and MIP1b circulating cytokines were observed in some patients at the highest doses (0.075, 0.1, 0.3 mg/kg) but a dose dependency has not been reached yet. Conclusions: Anti-KIR treatment is safe and well tolerated to date. At the 0.3mg/kg dose, MTD has not been reached, but a one week receptor blockade and signs of NK activation were observed. [Table: see text]
Contents, Vol. 48, 1987
Authors: Thomas Garrick, Afshin Veiseh, Yvette Taché, Herbert Weiner, Owen S. Surman, Jules L. Dienstag, Benedict Cosimi, Susan Chauncey, Paul S. Russell, D. Loldrup Poulsen, H.J. Hansen, M. Langemark, J. Olesen, P. Bech, Stephanie von Ammon Cavanaugh, D. Loldrup Poulsen, F. Zierau, L. Eplov, P.W. Jepsen, M. Kastrup, B. Kijne, S. Rasmussen, M. Stubgaard, P. Bech, Hoyle Leigh, G.G. Lloyd, Giovanni A. Fava, R.G. Laessle, S. Waadt, K.M. Pirke, Rosalyn A. Griffiths, Jennifer Holliday, S. Sato, Y. Sugiyama, S. Okuse, N. Yashiro, Giovanni A. Fava, George Molnar, Bruce D. Kirkcaldy, Elzbieta Kobylinska, E. Heim, K.F. Augustiny, A. Blaser, C. Bürki, D. Kühne, M. Rothenbühler, L. Schaffner, L. Valach, Daphne Glaun, Doreen Rosenthal, Michael von Rad, Almuth Sellschopp, Susan E. Abbey, Z.J. Lipowski, Mary Gutmann, Rob Sanson-Fisher, Bruce Christiansen, Barry Blackwell, Hans W. Künsebeck, Hellmuth Freyberger, David M. Garner, Paul M. Copeland, David B. Herzog, S.W. Touyz, P.J.V. Beumont, S.M. Dunn, Bertram Dippel, Christoph Lauer, Dieter Riemann, Katrin Majer-Trendel, Jürgen-Christian Krieg, Mathias Berger, David M. Garner, Paul E. Garfinkel, Wendi Rockert, Marion P. Olmsted, J.-C. Krieg, C. Lauer, K.M. Pirke, G.F. Huon, M. Wootton, G.G. Lloyd, J.M. Steel, R.J. Young
Journal: Psychotherapy and Psychosomatics (1987)
Phase I/II study of intratumoral injection of SD-101, an immunostimulatory CpG, and intratumoral injection of ipillumumab, an anti-CTLA-4 monoclonal antibody, in combination with local radiation in low-grade B-cell lymphomas.
Authors: Michael Siavash Khodadoust, Michael Patvin Chu, Debra Czerwinski, Kathleen McDonald, Steven Long, Holbrook Edwin Kohrt, Richard T. Hoppe, Ranjana H. Advani, Robert Lowsky, Ronald Levy
Journal: Journal of Clinical Oncology (2015)

TPS8604 Background: Immunotherapy is a promising treatment modality for low grade non-Hodgkin’s lymphomas. SD-101 (Dynavax Technologies) is an immunostimulatory synthetic CpG molecule that activates toll-like receptor 9. Intratumoral CpG injection produced local and abscopal anti-lymphoma immune responses with minimal systemic toxicity in an early phase clinical trial (Brody J et al. J Clin Oncol. 2010). Resistance to CpG is thought to be due to the induction of immune tolerance following an initial immune stimulation. Ipilimumab (Bristol-Myers Squibb) is a monoclonal anti-CTLA-4 antibody that interrupts inhibitory signaling on the surface of T cells, thus blocking the development of immune tolerance. Preclinical models show intratumoral injection of anti-CTLA-4 antibodies can produce systemic anti-tumor immune responses at a fraction of the standard systemic dose, thereby limiting adverse autoimmune side effects. This trial proposes a local low-dose immunomodulation strategy combining intratumoral CpG, intratumoral ipilimumab, and local radiation to produce systemic immune responses with minimal toxicity. Methods: Up to 12 patients will be enrolled in the phase 1 dose escalation design to determine maximum tolerated dose of intratumoral ipilimumab with a set dose of SD-101, and an additional 15 patients will be enrolled in the phase II expanded cohort at the chosen ipilimumab dose. All patients initially receive two fractions of 2 Gy radiation. After radiation, patients receive intratumoral SD-101 (1mg) and ipilimumab (10mg or 25mg depending on dose cohort). Weekly SD-101 intratumoral injections continue for a total of 5 doses. The primary objective is to determine the safety and tolerability of increasing dose levels of intratumoral ipilimumab with SD-101. Eligible patients must have relapsed/refractory low grade B-cell lymphoma with a disease site amenable to intratumoral injection and a second measurable disease site to assess abscopal effects. This study is currently accruing and is supported by a grant from the NIH (CA188005). Clinical trial information: NCT02254772. Clinical trial information: NCT02254772.
Interim safety and clinical activity in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase 1 study of ramucirumab (R) plus pembrolizumab (P).
Authors: Ian Chau, Johanna C. Bendell, Emiliano Calvo, Rafael Santana-Davila, Jordi Rodon Ahnert, Nicolas Penel, Hendrik-Tobias Arkenau, Jing Yang, Jessicca Rege, Gu Mi, David Ferry, Roy S. Herbst, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2017)

102 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02443324) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 was classified as positive (≥1%) or negative using the DAKO PD-L1 22C3 IHC pharmDx assay. Two dosing regimens were evaluated, Cohort A (R 8 mg/kg on Days 1&amp;8) and Cohort B (R 10 mg/kg on Day 1), given with P 200 mg on Day 1 q3W. The primary objective was to assess safety and tolerability of adding R to P; preliminary efficacy will be examined. Results: As of 23-Jun-2016, 40 G/GEJ pts have been enrolled (Cohort A: n=23; Cohort B: n=17). First pt treated in Cohorts A and B were on 29-Feb-2016 and 26-Oct-2015, respectively. The median age was 59 y, 75% were male, 65% had ECOG PS of 1, 48% were PD-L1 positive, and 70% received study treatment as third or subsequent regimen. Median duration of treatment was 2.1 mo and 4.1 mo for Cohort A and B, respectively. All grades treatment-related AEs (TRAE) occurred in 31 (78%) pts and similar between cohorts; TRAEs in ≥10% of pts were fatigue (30%), infusion related reaction (12.5%), decreased appetite (12.5%), pruritus (10%), maculopapular rash (10%), and hypertension (10%). Ten (25%) pts had grade 3-4 TRAEs, most commonly colitis (7.5%) and hypertension (7.5%). One treatment-related death occurred (pneumocystis pneumonia and pulmonary sepsis). Preliminary efficacy data showed 3 of 40 (7.5%) pts (PD-L1 negative, n=1; PD-L1 positive, n=2) have responded (1 confirmed and 2 unconfirmed PR) to treatment with a 45% disease control rate. Median PFS was 2.10 mo (95% CI, 1.18 to 4.04) and 2.60 mo (1.38, NR) for Cohorts A and B, respectively. Fifteen (37.5%) pts, including all responders, remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.
Self-monitoring and reminder texts to increase physical activity after colorectal cancer (Smart Pace): A pilot trial.
Authors: Erin Van Blarigan, Katherine Van Loon, Stacey A. Kenfield, June M Chan, Yoshimi Fukuoka, Angela Laffan, Emily Mitchell, Hilary Chan, Daniela Rodriguez-Jaquez, Jeffrey A. Meyerhardt, Alan P. Venook
Journal: Journal of Clinical Oncology (2017)

166 Background: Colorectal cancer (CRC) survivors can improve their quality-of-life (QOL), and potentially survival, by engaging in physical activity. The aim of this pilot randomized controlled trial (RCT) is to determine the feasibility of a technology-based physical activity intervention for CRC survivors. Methods: 40 CRC survivors will be randomized (1:1) to a 12-week physical activity intervention (Fitbit Flex, daily text messages) or usual care. Eligible individuals must: 1) have stage I-III colon or rectal adenocarcinoma; 2) have completed therapy; 3) be considered cancer-free; 4) be English speaking; 5) have no contraindications to moderate physical activity; 6) engage in &lt; 150 min/week of moderate physical activity; and 7) have Internet and a phone that can receive text messages. Our primary outcomes are adherence (e.g., Fitbit wear time, text response rate) and acceptability assessed via survey. Secondary outcomes include change in physical activity via 7-days of ActiGraph GT3X+ accelerometers and QOL. Results: We have screened 350 individuals with stage I-III CRC at the University of California, San Francisco (UCSF) for eligibility. Of these, 181 (52%) were not eligible [non-English speaking (46%), ≥ 150 min/week of physical activity (22%), contraindications to physical activity (22%), not cancer-free (7%), did not own a mobile phone (2%)]. We invited the remaining 169 eligible CRC survivors to participate by mail, e-mail, phone, or in clinic; 76 (45%) actively declined and 59 (35%) did not respond after up to 3 contact efforts. As of October 2016, 34 CRC survivors have been randomized to intervention (n = 16) or control (n = 18). These individuals are: 55% female; 64% Non-Hispanic White; 73% have a 4-y college degree; and 64% work full-time. The median (IQR) age and BMI are: 56 (50, 65) y and 26.4 (23.2, 32.4) kg/m 2 , respectively. Conclusions: The results of this pilot study will inform a definitive RCT to determine whether a technology-based physical activity intervention improves QOL and survival after CRC diagnosis. Funding: This research was supported by the NIH (K07CA197077, KL2TR000143), Mt. Zion Health Fund and UCSF Helen Diller Family Comprehensive Cancer Center.