tbuckley/cabot-search huggingface dataset:
Development of resistance to BET bromodomain inhibitor JQ1 and demonstration of epithelial-mesenchymal transition in pancreatic cancer cells.
Authors: Sania S. Raza, Mark Knab, Christina Chow, Krishan Kumar, Kazumi Ebine, Hidayatullah G. Munshi
Journal: Journal of Clinical Oncology (2014)

e15263 Background: Pancreatic ductal adenocarcinoma (PDAC) continues to be the leading cause of cancer related death in part due to limited efficacy of conventional chemotherapy. As such, there is increasing interest in developing inhibitors targeting epigenetic changes, including targeting BET proteins that bind acetylated histones to regulate gene transcription. We have found that the BET-inhibitor JQ1 is effective against pancreatic cancer cells. Since cancer cells can develop resistance to targeted therapies, we examined whether it was possible for PDAC cells to develop resistance to JQ1. Methods: The PDAC cell line CD18 cells (CD18-P) were treated with increasing concentration of JQ1 over a prolonged period of time to develop JQ1-resistent cells (CD18-JQ1r). We also generated CD18 cells resistant to 5-fluorouracil (CD18-CR) by treating CD18-P cells with increasing concentration of 5-fluorouracil. Results: Unlike CD18-P, CD18-JQ1r cells were resistant to the effects of JQ1 in 3D collagen. Moreover, JQ1 target genes c-MYC, FOSL1, and HMGA2, which are repressed in CD18-P cells treated with acute JQ1 treatment, were not repressed in CD18-JQ1R cells. When compared to the chemoresistant cells (CD18-CR) CD18-JQ1r showed less evidence of mesenchymal phenotype with lack of fibroblastic phenotype, repression of E-cadherin without expression of vimentin, repression of miR200 family of microRNA and upregulation of ZEB1. Additionally, CD18-JQ1r showed decreased cell matrix adhesion, lower levels of a2 and b1-integrin expression, and reduced FAK signaling. Transfection with ZEB1 siRNA restored cell-cell and cell-matrix adhesion defects seen in CD18-JQ1r cells. Moreover, ZEB1 siRNA partially repressed c-MYC, FOSL1 and HMGA2 in CD18-JQ1r cells. Conclusions: Pancreatic cancer cells can develop resistance to BET inhibitors. These resistant cells demonstrate defect in cell-cell and cell-matrix adhesion driven by ZEB1. Knockdown of ZEB1 can restore epithelial phenotype and enhance cell-cell and cell-matrix adhesion, and partly repress JQ1-target genes c-MYC, FOSL1 and HMGA2.
Unexpected pegensatide failure: Plea for an extension of an effective FDA early warning system.
Authors: Peter Georgantopoulos, Sony Jacob, Judy Nichols, Oliver Sartor, Richard M. Schulz, William J. Hrushesky, William N. Kelly, Charles L. Bennett
Journal: Journal of Clinical Oncology (2015)

e17625 Background: Historically, a mean of 11 years elapses before a Black Box warning is added to product labels of FDA approved drugs. It is unusual for a recently approved drug to be withdrawn from the market for safety reasons within 1 year of FDA approval. More unusual is for FDA withdrawal to occur when an unexpected toxicity develops in a very small number of patients. We reported in the New England Journal of Medicine (Bennett CL et al, NEJM) that the largest dialysis organization in the US initiated a pilot introduction of peginesatide amongst chronic kidney disease patients in 10 dialysis centers. We now report a comparison of the quality, completeness, and timing of the 28 adverse event reports submitted to the FDA from the pilot introduction versus the 10 reports submitted to the FDA from centers that did not participate in the pilot introduction. Methods: The pilot introduction was conducted at 10 LDO centers, a nurse funded by the manufacturer of peginesatide was assigned to each center to facilitate data collection, and dialysis staff was educated on peginesatide dosing, safety, pharmacokinetics, and handling. Reports to the FDA of anaphylaxis that occurred in the pilot introduction versus other sites were reviewed. Results: In comparison to 28 anaphylaxis-hypotension events reported to the FDA from the pilot introduction, the10 anaphylaxis-hypotension reports to the FDA from settings not participating in the pilot introduction were less often reported as fatal (0% versus 22%) or grade IV severity (10% versus 22%), associated with hypotension (20% versus 57%), or cardiorespiratory arrest (0% versus 29%); and were reported to the FDA later (median of 81 days (range, 14- 172) versus 46 days (range, 4 – 136 days). Onset was a median of 4 to 5 minutes after peginesatide infusion in either setting. Conclusions: Had the pilot introduction not been conducted, it is unlikely that the toxicity of severe anaphylaxis-hypotension would have been uncovered for several more years. With the expected rollout of biosimilars for epoetin in the next year, pilot introductions similar to that which was established for peginesatide, should be developed.
Preliminary safety and efficacy of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (IBR) in patients (pts) with hairy cell leukemia (HCL).
Authors: Jeffrey Alan Jones, Leslie A. Andritsos, David M Lucas, Gerard Lozanski, Terri Hutchinson, Jennifer L. Sexton, Pamela Jo Harris, Michael R. Grever
Journal: Journal of Clinical Oncology (2014)

7063 Background: Effective treatments (tx) for classical (c) HCL pts refractory to or ineligible for nucleoside analogs (NA) are limited, and there is no accepted standard for either tx-naïve or relapsed variant (v) HCL. IBR, an oral small molecule inhibitor of BTK, is active in several indolent B-cell malignancies, but its activity in HCL has not been previously assessed. We report preliminary safety and efficacy data from a CTEP-supported phase 2, multicenter study. Methods: Pts with cHCL (relapsed after ≥1 NA or unfit for NA) and vHCL who require tx are eligible if ECOG ≤2, free of infection and end-organ function preserved. Pts receive continuous IBR 420 mg daily in 28-day cycles. Response, including bone marrow biopsy with immunohistochemistry for MRD, is assessed after 8 and 12 cycles. Pts may continue IBR indefinitely absent unacceptable toxicity or progressive disease. Results: 8 pts (1 tx-naïve and 1 relapsed vHCL, 6 relapsed cHCL) have been dosed (range 1-8 cycles) and all remain on tx. Common treatment-related adverse events were grade (Gr) 1/2 diarrhea, rash, arthralgia/myalgia, and transient Gr 1-3 elevation of hepatic transaminases. 3 cases of Gr 3 neutropenia and 2 cases of febrile neutropenia have been observed during cycle 1, all responding to tx interruption and/or brief course GCSF. Redistribution lymphocytosis (peaking at day 8) occurred in both vHCL pts and 1 V34.4 subtype cHCL pt with circulating disease at baseline. Soluble IL2 receptor (sIL2R) levels decreased after tx in all pts and correlated with improvements in symptoms and peripheral blood counts. Marrow clearance (>90% pre-, <2% post-tx) was observed in the first pt undergoing response assessment after 8 cycles. Pretreatment imunoblots demonstrated the presence of pBTK in several pts that was substantially reduced after IRB. This did not correlate with loss of pERK, suggesting that ERK phosphorylation ex vivo may not be a reliable indicator of IBR activity. Conclusions: IBR appears well tolerated and demonstrates early evidence of activity in both cHCL and vHCL. sIL2R levels may correlate with response. Accrual continues at 5 US sites. Updated safety and efficacy data will be presented. Clinical trial information: NCT01841723.
A phase II and biomarker study of an irreversible pan-human EGF receptor (HER) tyrosine kinase inhibitor dacomitinib in patients with recurrent and/or metastatic squamous cell carcinoma of esophagus.
Authors: Hyo Song Kim, Han Sang Kim, Jong-Mu Sun, Myung-Ju Ahn, Keunchil Park, Hoon-Gu Kim, Ik-Joo Chung, Jong-Seok Lee, Se-Hoon Lee, Kyung Hee Lee, Dae Joon Kim, Hye Ryun Kim, Joo-Hang Kim, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2014)

4083 Background: Dacomitinib is an oral irreversible tyrosine kinase inhibitor of EGFR, HER2 and HER4 signaling. The goals of this study were to investigate the clinical activity, safety and predictive biomarkers of dacomitinib in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: Forty-nine patients with advanced ESCC, who had failed one line of prior platinum-based chemotherapy, were administered dacomitinib 45mg/day. The primary endpoint was objective response rate and predictive biomarkers were evaluated using tumor material obtained before dacomitinib treatment. We characterized somatic mutations using the Ion AmpliSeq platform (2,800 mutations from 50 genes), gene copy number (86 genes) and gene expression (230 genes) using NanoString nCounter. Results: The median age was 64 years (range 47-83) and the majority of patients were male (93.3%), had 0-1 ECOG performance status (91.8%). In terms of previous chemotherapy, 40 (81.3%) and 9 (18.4%) patients received 1 and 2 prior chemotherapy, respectively. Of the 48 evaluable patients, 10 (20.8%) achieved partial responses (PR), of these, 6 (12.2%) showed confirmed PRs. Twenty-nine patients (61.2%) had stable disease. The median treatment duration is 82 days (range 16-335 days), and main reason of treatment discontinuation was progression (n=34, 69.4%) and toxicity (n=4, 8.2%). Seven (14.3%) patients are on treatment and they are all progression free more than 120 days. Among the 34 patients with progression, the median time to progression was 80 days (95% CI, 59-102 days). With a median 169 days of follow up, the median overall survival was 4.5 months (95% CI, 3.1-6 months). Nineteen patients (38.8%) had treatment interruption due to toxicity, and 14 (28.5%) of them had dose reduction. The most common dacomitinib-related adverse effects were diarrhea (69.4%) followed by rash (57.1%). Conclusions: Dacomitinib demonstrated promising efficacy with manageable toxicity in platinum-failed ESCC patients. We attempted to identify predictive biomarker for dacomitinib treatment. Updated clinical outcome and final biomarker data will be presented at ASCO 2014. Clinical trial information: NCT01608022.
Evaluation of sexual function on a randomized trial of a prostate rectal spacer.
Authors: Daniel A. Hamstra, Dhiren Shah, Steven Kurtzman, John Sylvester, Shawn H. Zimberg, Richard S. Hudes, Lawrence Ivan Karsh, Mark D. Logsdon, David Beyer, Michael Kos, R. Alex Hsi, Kevin Forsythe, Edward M Soffen, Patrick M Francke, Hong Zhang, Theodore L. DeWeese, Rodney J. Ellis, Jeffrey Bogart, Constantine Mantz, Neil Mariados
Journal: Journal of Clinical Oncology (2017)

69 Background: The SpaceOAR phase 3 trial showed that a hydrogel spacer between the prostate and rectum decreased rectal dose and toxicity while improving bowel quality of life (QOL) after image guided prostate IMRT to 79.2 Gy. Here we evaluated dose to penile bulb as well as sexual function on this trial Methods: Sexual QOL was measured with the Expanded Prostate Cancer Index Composite (EPIC) by mean summary scores and the proportion of patients with a minimally important decline (MID) (11 points). Stratification was based on severe erectile dysfunction (ED)(EPIC &lt; = 60) vs not. The single question on “Erections sufficient for intercourse over the preceding 4 weeks” was also evaluated. Results: Median Follow-up was 37 months with 63% of men evaluable at 3 years. With spacer the dose to the penile bulb was reduced for mean (21 vs 11 Gy), Dmax (46 vs 36 Gy), and V10-V30 (all p &lt; 0.05). Baseline sexual function was 53 (±24) with 54% having severe ED with no difference between arms (p &gt; 0.1). At 3 years average EPIC score was 39.7 (± 23) and 82% had severe ED with no differences between arms (p &gt; 0.1). At enrollment 42% had EPIC &gt; 60 with average summary of 77 (±8.3) which at 3 years was 53 (±24.8). In this sub-group at 3 years a higher EPIC was observed on the Spacer arm (57.7 (±24.1) vs. 44.6 (± 24.4)) which met the threshold for an MID without statistical significance (p = 0.07). Based on MID and twice that there was a trend favoring Spacer with 53% vs 75% for 11-point decline (p = 0.064) and 41% vs 60% for 22 point decline (p = 0.11). A small number of these men were potent at baseline and evaluable both at baseline and 3 years (n = 49). Of these 37.5% in the Control arm had erections sufficient for intercourse at 3 years as compared to 66.7% (p = 0.07) in the Spacer arm. Power analysis revealed 35% power to detect a change of 11 points between arms and 27% power to detect a difference of 22 points. Conclusions: The use of a hydrogel spacer decreased dose to the penile bulb with a suggestion of a clinically significant improvement in patient reported sexual function and potency. These did not achieve statistical significance potentially due to the high prevalence of ED at baseline and, therefore, the small evaluable sample size. Analysis of penile bulb dose and QOL is ongoing. Clinical trial information: NCT01538628.
Imaging biomarker in phase I trials: DCE-US and early evaluation of antiangiogenic treatments.
Authors: Romain Cohen, Serge Koscielny, Jean-Charles Soria, Jean-Pierre Armand, Baya Benatsou, Nathalie Lassau
Journal: Journal of Clinical Oncology (2013)

e22153 Background: The French prospective STIC study (Support for Innovative and Expensive Techniques) of dynamic contrast enhanced-ultrasonography (DCE-US) with quantification for evaluation of anti-angiogenic treatments showed that a decrease of 40% of AUC is predictive of response in 539 patients treated with approval drugs. The objective was to evaluate the decrease of AUC DCE-US at one month as a predictive imaging biomarker for time to progression (TTP) in phase I trials using anti-angiogenic agents. Methods: Patients included in phase I in our institution from 2007 and evaluated with DCE-US were retrospectively reviewed. Patients were evaluated at baseline and 1 month with the same standardized methodology: a bolus injection of contrast medium, 3 minutes of recorded raw linear data with 4 frames per second and the quantification using ESFUMB guidelines. All data were prospectively stored in a centralized database. TTP was calculated according to RECIST criteria and clinic. A decrease of more than 40% of AUC at one month was challenged to be predictive of TTP. Results: In the preliminary results concerning 26 patients, 6 had a decrease of more than 40% of AUC at one month with a median TTP of 5.5 months. The 20 others without a strong decrease of AUC had a TTP less than 2 months. The decrease of AUC was correlated to TTP (p=0.004). Eighty one supplementary phase I patients are under radiological blind review and will be included for presentation at ASCO. Conclusions: The decrease of more than 40% of AUC at one month could be a predictive biomarker of response to anti-angiogenic treatments in phase I. The final results will be presented with 107 patients. Considering the toxicity risk for the patients and the cost of anti-angiogenic drugs, such a simple and cheap imaging biomarker should be considered to maintain or not the treatment after US evaluation of the first cycle.
Is conversion to resection possible with hepatic arterial infusion (HAI) and systemic (SYS) even in previously treated patients (pts) with unresectable colorectal liver metastases (UnCLM)?
Authors: Nancy E. Kemeny, Yuman Fong, Philip Paty, Joanne F. Chou, Marinela Capanu, Alexandra N. Gewirtz, William R. Jarnagin, Ronald P. DeMatteo, Peter J Allen, T. Peter Kingham, Celina Ang, Andrea Cercek, Michael Ian D'Angelica
Journal: Journal of Clinical Oncology (2012)

3577 Background: Previously, we showed thatHAI with FUDR + dexamethasone (Dex) plus SYS produced a 47 % resectability rate in a retrospective study of 49 pts with UnCLM. Methods: Prospectively evaluated UnCLM pts in a new protocol were combined with the above protocol (n=105 pts) and all were treated with HAI FUDR/Dex + Sys. Unresectability was defined as diffuse bilateral metastases, involvement of all hepatic/portal veins, and/or inability to preserve remaining liver with adequate perfusion. Factors associated with conversion were identified using a multivariate logistic regression model. Overall survival (OS) and progression free survival (PFS) were calculated from pump placement by the Kaplan-Meier method. Resectability was a time-dependent covariate in a Cox regression model. Results: 61 of the 105 pts had prior SYS (56 %with prior Oxali) and 45 (74%) were progressing at the time of pump placement. In previously treated pts, 44% underwent resection, with a median OS of 45 mos. Of 44 chemo-naïve pts, 57% underwent hepatectomy, with a median OS of 68 mos. The following were significantly associated with resection conversion: lesion number [p=0.02], baseline CEA [p=0.04], females [p=0.03] and clinical risk score (CRS) [p=0.05]. In multivariate analysis, gender and CRS remained predictive of resectability. Surgery greatly reduced the hazard of death by 67% [HR: 0.33, 95%CI: 0.17-0.61, p=0.0004], after adjusting for several risk factors (Table). Median PFS was 12 mos for all pts. Conclusions: Even in previously treated pts,HAI + SYS is an approach to convert UnCLM to resection. Gender and CRS are associated with conversion to resectability. [Table: see text]
The Diterpenoid Lactone Andrographolide Induces Reactive Oxygen Species (ROS) Dependent Apoptosis in ATRA Sensitive and Resistant APL Cell Lines.
Authors: Shuo Yang, Jessica K. Altman, Sheila Prachand, Austin Tom, Bo Ding, Brent Wu, Leonidas C. Platanias, Leo I. Gordon
Journal: Blood (2012)
A phase II study of oral ENMD-2076 administered to patients (pts) with advanced soft tissue sarcoma (STS).
Authors: Herbert H. F. Loong, Martin E. Blackstein, Abha A. Gupta, David Hogg, Helen Mackay, Neesha C. Dhani, Amit M. Oza, Malcolm J. Moore, Albiruni R.A. Razak
Journal: Journal of Clinical Oncology (2013)

TPS10593 Background: The use of angiogenic and Aurora kinase inhibitors has been shown to abrogate tumour growth in STS. ENMD-2076 is an oral Aurora A and angiogenic kinase inhibitor that has demonstrated single-agent activity in sarcoma cell lines. Prior phase I dose escalation study has determined the maximum tolerated dose of ENMD-2076 to be 160mg/m 2 , with a recommended starting dose of 275mg/day. In that study, one patient with STS experienced durable stable disease (21 months). Primary Objective: To determine the activity of ENMD-2076 in advanced STS (with ≤1 prior line of therapy) as defined by 6-month progression-free survival rate (PFSR). Secondary Objectives: (i) To determine the safety and tolerability of ENMD-2076, (ii) To determine the objective response rate (ORR) as per RECIST criteria and duration of response, (iii) To perform exploratory analysis of factors associated with survival. Study Design and Methodology: This is a single-center, open-labeled phase II study of ENMD-2076 in advanced STS. Pts are commenced on 275 mg daily dose on a 28 day cycle. Treatment-emergent adverse events will be assessed by the NCI-CTCAE (4.0). Radiographic or clinical tumour measurements will occur every 2 cycles. Sample Size Justification: It is assumed that ENMD-2076 shall be deemed non-efficacious in this population if the true 6- month PFSR probability is &lt;15% (p0), whilst a 6-month PFSR probability &gt;40% will be considered positive for activity. This translates to a minimum of 21 evaluable subjects required in the study, within which ≥6 patients need to have shown lack of progression at 6 months in order for this study to be considered positive. This design has a significance level of 10% and power of 90%. Methods: PFSR at 6-months will be estimated using the Kaplan-Meier method. ORR will be estimated and 2-sided 95% exact binomial confidence interval will be provided. Study Progress: At deadline for abstract submission, 3 patients have been enrolled onto this study. Clinical trial information: NCT01719744.
Outcome of definitive treatment of adenoid cystic carcinoma in the head and neck.
Authors: Jin Ho Kim, Joo Ho Lee, Hong-Gyun Wu, Charn Il Park, Myung-Whun Sung, Kwang Hyun Kim, Tack-Kyun Kown, Jeong-Hun Hah, Se-Hoon Lee
Journal: Journal of Clinical Oncology (2014)

e17025 Background: To retrospectively analyze treatment outcome in patients with adenoid cystic carcinoma (ACC) in the head and neck. Methods: Total 171 patients with previously untreated ACC in the head and neck underwent curative treatments between 1981 and 2010. Treatments were surgery in 26 (15%), radiotherapy (RT) in 28 (16%), and surgery followed by RT (combined modality treatment) in 117 patients (69%). Results: The 10-year overall-survival (OS), disease-free survival (DFS), locoregional-relapse-free survival (LRFS), and distant-metastasis-free survival were 51.7%, 18.4%, 32.6%, and 27.7%, respectively. Recurrence was detected in 110 patients: locoregional in 25, distant in 44, and both in 41. Multivariate analysis showed that the combined modality treatment was significantly associated with better DFS (p=.016) and LRFS (p<.001) compared to RT or surgery alone. Even among 49 patients with T1/T2 tumors without perineural invasion, the combined modality treatment group (n=36) had better local control than the surgery alone group (n=13) (p=.008). Five-year survival rates after first recurrence were 46% and 50% for distant metastases and locoregional failures, respectively (p=.112). Conclusions: Regardless of stages, a combined modality treatment is recommended as curative treatment for head and neck ACC. Given the high rates of distant metastases and protracted survival, the effective systemic treatment is needed to make a breakthrough for the treatment of ACC in the head and neck.
Radiographic parameters in predicting outcome of patients with nonsquamous non-small cell lung cancer (NSCLC) treated with bevacizumab.
Authors: Michael R Kaufman, Mohamed E. Salem, Hussein Aoun, Gregory Peter Kalemkerian, Sara Kunz, Sherif El-Refai, Praveen Ranganath, Ammar Sukari, Shirish M. Gadgeel, Antoinette J. Wozniak
Journal: Journal of Clinical Oncology (2013)

e19009 Background: Bevacizumab has increased survival in NSCLC patients (pts) when added to standard chemotherapy. However, whether radiographic features at baseline and/or post-treatment can predict benefit from addition of anti-angiogenic therapy to standard chemotherapy remains unknown. In addition, the impact of VEGF-targeted therapy on CT parameters is not fully characterized. Methods: A retrospective review was performed using CT scans of pts enrolled into a prospective phase II clinical trial of pemetrexed, gemcitabine and bevacizumab in stage IV chemo-naïve, non-squamous, NSCLC pts (Wozniak A, et al. IASLC2011). Treatments were repeated every 2 wks (1 cycle). CT scans were obtained at baseline and at the end of every 4 cycles. The radiographic CT features of the primary tumors were retrospectively reviewed at baseline and after first 4 cycles. RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria were used to assess tumor radiographic response. Results: Twenty-four pts (43% males; median age, 62 y [range: 41-82]), were evaluable for this analysis. On baseline CT, median tumor size was 2.9 cm (range: 1.6. to 6.3 cm), median attenuation was 56 HU (range: 31 to 87 HU), 81% of tumors had heterogeneous enhancement, and 50% of tumors demonstrated invasion of adjacent structures. Well-defined margins were noted in 43% of tumors and 81% had &lt; 30% necrosis. On post-4 cycle CT, 63% of tumors had decreased long diameter (median 15% decrease), 81% had decreased attenuation (median 21% HU reduction) and 50% had increased necrosis. RECIST-defined PR was seen in 37%, SD in 56%; and PD in 1 (4%) based on size despite &gt; 75% necrosis. MASS criteria response was favorable in 25% and non-favorable in 75% of tumors. Pts with tumors that demonstrated FR response by MASS after 4 cycles were more likely to have prolonged progression free survival (HR 2.94; p= 0.175). Conclusions: In tumors treated with anti-angiogenic therapy, imaging response criteria that include changes in tumor morphology, attenuation, and size may capture anti-tumor effect more accurately than size-based RECIST criteria alone. These results support the need for prospective investigation of the efficacy of MASS criteria.