tbuckley/cabot-search huggingface dataset:
C-1311, a novel inhibitor of FLT3 and topoisomerase II: A phase 1 trial of a once every three week schedule in patients with advanced solid tumors
Authors: A. L. Thomas, A. Anthoney, E. Scott, S. Ahmed, A. S. Lundberg, A. Major, R. L. Capizzi, C. J. Twelves
Journal: Journal of Clinical Oncology (2008)

2576 Background: C-1311 (Symadex) is a lead compound in the novel class of imidazoacridinones, inhibitors of both topoisomerase II and certain receptor tyrosine kinases (RTK) including FLT3, being tested for the treatment of cancer and autoimmune diseases. This phase 1 trial assessed safety, determined the maximum tolerated dose (MTD) and recommended dose (RD) of C-1311 in patients (pts) with advanced solid tumors. Methods: Pts with tumors refractory to conventional therapy were enrolled. The dosing schedule was a 1-hr infusion daily for 5 consecutive days every 3 weeks (dx5), subsequently amended to once every 3 weeks (q3w). The maximum tolerated dose (MTD) is where 2 or more of at least 3 pts experience dose-limiting toxicity (DLT). The recommended dose (RD) is the dose level below the MTD. An expanded RD cohort of 9 pts was also evaluated. Systemic pharmacokinetics were assessed. Results: 36 pts were treated. No DLTs were observed in the first 5 single patient cohorts on a dx5 schedule at 6, 12, 24, 48 and 96 mg/m2/day. Subsequent pts were treated in 3+3 patient cohorts at 640, 850 and 1,100 mg/m2, and 950 mg/m², which was the MTD. All DLT were hematologic, reversible neutropenia and occasional thrombocytopenia. Grade 3 and 4 neutropenia was observed in 19% and 17% of pts in the first treatment cycle (no associated sepsis). No cumulative toxicity was observed. Nonhematologic treatment-related adverse events (AEs) were lethargy (75%), nausea (50%), vomiting (44%), neutropenia (36%), dizziness (31%) and fatigue and infusion site pain (22% each), with grade 3/4 AEs being lethargy, atypical pneumonia, and dyspnea in one patient (3%) each. No nonhematologic DLT or abnormal LVEF were observed. Partial response and stable disease (SD) were observed in 1 (3%) and 17 (47%) pts. Conclusions: C1311 is a novel imidazoacridinone targeting both topoisomerase II and FLT 3 family of RTK. The RD on a q3w schedule of 850 mg/m2 has acceptable safety. DLT is only reversible dose-related neutropenia. SD in heavily pretreated pts with sarcomas and epithelial malignancies suggests preliminary evidence of antitumor activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Xanthus Pharmaceuticals Xanthus Pharmaceuticals
Adjuvant sunitinib (Su) for locally advanced esophageal cancer (LAEC): Results of a phase II trial.
Authors: J. J. Knox, R. Wong, G. E. Darling, J. Lister, M. Guindi, G. Liu, W. Xu, J. J. Kim, D. J. Jonker, J. Wells, W. Kendal, H. Mackay, A. Visbal, R. E. Dinniwell, A. Pierre, R. Feld, S. Sundaresan, A. Bayley, Y. Shargall, A. M. Horgan
Journal: Journal of Clinical Oncology (2011)

4091 Background: Despite trimodality therapy the prognosis for LAEC is poor. Adjuvant anti-VEGF strategies are under study in many cancers. In this completed phase II trial we report tolerability and efficacy of Su, a multitargeted tyrosine kinase inhibitor, following chemoradiation and surgery for LAEC. Methods: Included were patients (pts) with LAEC of the thoracic esophagus (TE) or gastroesophageal junction (GEJ), stages IIa to III, and ECOG PS ≤1. Treatment pre-op was Irinotecan (65mg/m2) + Cisplatin (30mg/m2) on weeks 1,2,4,5,7,8 + concurrent EBRT (50Gy/25 fractions). Irinotecan was reduced to 50mg/m2 after 22 pts enrolled, due to neutropenia. Su 37.5 mg daily, with dose schedule modifications, started 4-13 weeks post op, for 1 year. Planned sample size: 36 pts on Su. Primary end-points were feasibility and efficacy (time to treatment failure, time to progressive disease, survival [OS]). Results: 70 pts were enroled from 11/06 - 12/10. Nine pts excluded with positive PET. Median age 60 yr (36-71), 80% male, 52% TE, 80% adenocarcinoma and 24 pts had stage IIA, 9 IIB, and 28 III disease. With 1 pending, 60 pts commenced chemoradiation. Three deaths occurred during induction – 2 treatment related. Esophagectomy was performed on 48 pts: 1 progressed pre-op, 2 unresectable at laparotomy, 5 surgically unfit and 1 pending. With pathology available on 42, complete pathological response was seen in 15 (36%). Su commenced on 32 pts, with 4 pending. Twelve (25%) did not start: poor PS (3), post op death (1), surgical complications (2), pt choice (1), early recurrence (5). Seven pts remain on Su. Of the 25 who stopped Su, mean duration of treatment was 5.5 mths with 4 (16%) completing 12 mths. Thirteen (52%) discontinued with progressive disease and 7 (28%) with toxicity. At a median follow-up of 13 mths, 17/48 surgical pts have died, with a median OS of 26 mths and 2 yr OS of 50%. At a median follow-up of 15.5mths, 10/32 pts who started Su have died, with a median survival of 26 mths and 2 yr OS of 53%. Conclusions: Pt morbidity after trimodality therapy limited the feasibility of starting-, and the tolerance to- Su, which was associated with toxicity in this adjuvant setting despite optimal supportive care. Complete efficacy outcomes to be presented.
Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3‐kinase P110d, in patients with previously treated chronic lymphocytic leukemia.
Authors: S. E. Coutre, J. C. Byrd, R. R. Furman, J. R. Brown, D. M. Benson, N. D. Wagner-Johnston, I. W. Flinn, B. S. Kahl, S. E. F. Spurgeon, B. J. Lannutti, H. K. W. Hsu, R. Ulrich, S. Peterman, L. Holes, L. L. Miller, A. S. Yu
Journal: Journal of Clinical Oncology (2011)

6631 Background: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin. CAL-101 is an isoform-selective inhibitor of PI3Kδ that induces apoptosis of chronic lymphocytic leukemia (CLL) cells. Methods: This phase I study evaluated CAL-101 in patients with previously treated hematologic cancers. CAL-101 was administered orally 1 or 2 times per day (QD or BID) continuously in 28-day cycles, until disease progression or unacceptable toxicity. Efficacy analyses were based on standard criteria. Results: At data cutoff, the study had enrolled 54 patients with CLL. Patient characteristics included: median [range] age of 62 [37‐82] years; 82% males; 72% with refractory disease, 81% with bulky disease, 36% with del(17p), and a median [range] of prior therapies of 5 [2‐15]. CAL-101 dose levels were 50 mg, 100 mg, 150 mg, 200 mg, and 350 mg BID; and 300 mg QD. The median [range] of CAL‐101 treatment cycles was 8 [1-19]. Grade ≥3 adverse events included pneumonia (24%), neutropenia (24%), thrombocytopenia (7%), neutropenic fever (7%), anemia (6%) and ALT/AST increase (6%). CAL‐101 reduced lymphadenopathy by ≥50% in 80% of patients. A transient increase of >50% from baseline in peripheral absolute lymphocyte counts occurred in 58% of patients. The overall intention-to-treat response rate by IWCLL 2008 criteria was 26%. Medians for duration of response and progression-free survival had not been reached (>11 months), with 46% of patients continuing on treatment. CAL-101 reduced constitutive overexpression of phospho‐AKT in patient CLL cells and normalized plasma concentrations of CCL3, CCL4, and CXCL13. PK analyses showed minimal increases in plasma Cmax and AUC at doses >150 mg BID. Accrual is ongoing and updated data will be presented. Conclusions: CAL-101, an oral PI3Kδ-selective inhibitor, shows acceptable safety and promising clinical activity in heavily pretreated patients with CLL. Dose‐response assessments support the 150 mg BID dose for future single-agent and combination chemo/immunotherapy studies.
PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation
Authors: Wen Zhang, Jieliang Chen, Min Wu, Xiaonan Zhang, Min Zhang, Lei Yue, Yaming Li, Jiangxia Liu, Baocun Li, Fang Shen, Yang Wang, Lu Bai, Ulrike Protzer, Massimo Levrero, Zhenghong Yuan
Journal: Hepatology (2017)

Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The covalently closed circular DNA (cccDNA) minichromosome, which serves as the template for the transcription of viral RNAs, plays a key role in viral persistence. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation of cccDNA‐bound histone 3 (H3) and H4, the potential contributions of histone methylation and related host factors remain obscure. Here, by screening a series of methyltransferases and demethylases, we identified protein arginine methyltransferase 5 (PRMT5) as an effective restrictor of HBV transcription and replication. In cell culture–based models for HBV infection and in liver tissues of patients with chronic HBV infection, we found that symmetric dimethylation of arginine 3 on H4 on cccDNA was a repressive marker of cccDNA transcription and was regulated by PRMT5 depending on its methyltransferase domain. Moreover, PRMT5‐triggered symmetric dimethylation of arginine 3 on H4 on the cccDNA minichromosome involved an interaction with the HBV core protein and the Brg1‐based human SWI/SNF chromatin remodeler, which resulted in down‐regulation of the binding of RNA polymerase II to cccDNA. In addition to the inhibitory effect on cccDNA transcription, PRMT5 inhibited HBV core particle DNA production independently of its methyltransferase activity. Further study revealed that PRMT5 interfered with pregenomic RNA encapsidation by preventing its interaction with viral polymerase protein through binding to the reverse transcriptase–ribonuclease H region of polymerase, which is crucial for the polymerase–pregenomic RNA interaction. Conclusion : PRMT5 restricts HBV replication through a two‐part mechanism including epigenetic suppression of cccDNA transcription and interference with pregenomic RNA encapsidation; these findings improve the understanding of epigenetic regulation of HBV transcription and host–HBV interaction, thus providing new insights into targeted therapeutic intervention. (H epatology 2017;66:398–415).
Understanding total cost of cancer care to determine strategic interventions to improve value.
Authors: Kerin B. Adelson, Salimah Velji, Kavita Patel, Basit Chaudhry, Sonia Grizzle, Catherine A. Lyons, Rogerio Lilenbaum
Journal: Journal of Clinical Oncology (2016)

3 Background: Cancer centers across the country are largely unprepared to move toward value-based payment. Total cost of care data is not readily available and centers do not know how much of their patients’ care is received at other hospitals, when in the trajectory of illness greatest cost is incurred, or the elements of care that present the greatest opportunity for savings. A previous examination of practice patterns Smilow Cancer Hospital (SCH) demonstrated that our patients had high rates of ED visits, hospital admissions and ICU use in their last month of life. While this data is consistent with other large academic cancer centers (AMCs), there is a clear opportunity to improve our end-of-life planning and reduce futile care. Cost data supplemented the overutilization analysis, informing the infrastructure investments to prepare us for value-based payment models. Methods: We accessed the 5% Medicare Limited Dataset (2012-2013) to map out cost of care in 6-month episodes for all Medicare patients receiving chemotherapy. Patients who had received chemotherapy at a SCH site were flagged and the analysis included all cost of care, regardless of the site of service or type of professional delivering the service. Results: On average, a first episode of care at SCH cost $26,500, a second episode $38,000 and a third $45,600. Our analysis demonstrated important associations between increases in spending and ED utilization. Patients who had 1 or fewer ED visits during an episode, averaged $21,000 vs. $49,000 for those with 2 or more. Patients who died during an episode cost $53,000 compared to $25,600 for patients who lived. SCH episodes were significantly more expensive than CT, and slightly more than a comparable east coast Academic Medical Center. Conclusions: The above demonstrates that aggressive treatments, ED visits and hospital admissions at the end-of-life are major cost drivers. We used the analysis to target infrastructure investments in Urgent Care to reduce ED utilization, Care Management to prevent hospital admissions/readmissions and early referral to Palliative Care for clarification of goals of care. We believe these investments will lead to significant cost reductions.
Effectiveness of darbepoietin-alpha (Nesp) in patients undergoing autologous peripheral blood stem cell transplantation (PBSCT)
Authors: M. Martino, F. Morabito, I. Callea, A. Pontari, P. Gasparone, P. Borruto, G. Longo, D. Marcuccio, G. Console, P. Iacopino
Journal: Journal of Clinical Oncology (2005)

6673 Background: Nesp is a relatively new long-acting erythropoietin, with a half-life three times longer than the old epoietins. Extensive studies indicate that Nesp can be administered far less frequently than other epoietins, with an equivalent erythropoietic effect. Therefore, Nesp may help address some of the unmet needs of anemia treatment in patients undergoing PBSCT. Methods: 26 recipients of a PBSCT [11 males 15 females, aged 23–69 years (median age, 56 years)] entered this study. They had mainly a diagnosis of multiple myeloma or lymphoma. Patients received ≥5 x 106 CD34+ PBSCs/kg on day 0 and G-CSF from day 3 until neutrophil engraftment. The median nadir of Hb levels after PBSCT was 7.9 g/dL. Nesp (150 micro g total dose/weekly) was initiating in two-four weeks after PBSCT, with the aim of achieving Hb levels of 13 g/dl. This initial Hb target was chosen to ensure easy maintenance of Hb values above 12 g/dl thereafter. Complete blood counts, serum soluble transferrin receptor and serum erythropoietin (EPO) levels were measured at the time of Nesp start. Moreover, Hb levels were weakly determined until Nesp withdrawal. Results: At Nesp start, the median Hb level was 10 g/dL (range Hb 8.1–11.5 g/dL), while serum EPO levels was 97 mU/ml (range 9–316 mU/ml). All patients responded to Nesp therapy over a period of 8 weeks. The overall median time to reach the target Hb level of 13 g/dL was 5 weeks, with no case responding after the first 2 weeks of Nesp therapy. A significant slower response to Nesp therapy was experienced by those patients starting with Hb levels below 10 g/dL [4 weeks (CI 3–5 weeks) versus 5 weeks (CI 3–7 weeks), p=0.05] and with serum EPO levels above 50 mU/ml [4 weeks (CI 3–5 weeks) versus 6 weeks (CI 5–7 weeks), p=0.0098]. Response to Nesp failed to be significantly associated with any other variable. Conclusions: This is the first report showing that Nesp is effective in allowing anemic patients to reach optimal Hb levels after PBSCT with fairly timeliness. Future studies should set a more rational use of this expensive drug, investigating the impact of Nesp therapy on transfusion requirements and QoL, thus ameliorating its cost/effectiveness ratio in the setting of autologous PBSCT. No significant financial relationships to disclose.
PCA3 urine assay for prostate cancer in Japanese men undergoing prostate biopsy.
Authors: K. Okihara, A. Ochiai, Z. Fros, T. Miki
Journal: Journal of Clinical Oncology (2010)

4648 Background: Several studies using APTIMA PSA assay have demonstrated that PCA3 score is superior to serum PSA for predicting prostate cancer with high specificity in North American and European men undergoing biopsy. In this study, we examined the clinical utility of PCA3 urine test for prostate cancer in Japanese men undergoing prostate biopsy. Methods: The study group included 105 men who underwent extended prostate biopsy with serum prostate specific antigen (PSA) elevation. In all cases, race was Asian. Urine specimens were collected after digital rectal examination and PCA3 score (PCA3/PSA mRNA) was determined in the urine using APTIMA PCA3 assay. PCA3 score was correlated with serum PSA, prostate volume (PV) and biopsy outcome. Results: All urine samples collected were successfully analyzed (i.e., the informative specimen rate was 100%). Biopsy revealed prostate cancer in 38 men (36%). PCA3 score was not associated with serum PSA nor PV. Median PCA3 score in prostate cancer was significantly higher than that in negative biopsy (59.5 vs 14.2 p<0.001). The probability of prostate cancer was 69% at PCA3 score of more than 50 and 9% at PCA3 score of less than 20. Using a PCA3 cutoff value of 35, sensitivity and specificity were 68% and 80%. Area under the curve (AUC) for PCA3 score was 0.82 and AUC for serum PSA was 0.74. On multiple logistic regression, serum PSA (p<0.05), PV (p<0.01), and PCA3 score (p<0.005) were the independent predictors for prostate cancer. Conclusions: The specificity of PCA3 urine assay for prostate cancer was high in Japanese men undergoing biopsy. PCA3 score could improve the prediction for prostate cancer and help better select men who might benefit from prostate biopsy. No significant financial relationships to disclose.
Hypersensitivity reactions to cetuximab.
Authors: L. R. Duska, M. S. Henretta, M. Hobbs, T. Platts-Mills, P. M. Fracasso
Journal: Journal of Clinical Oncology (2011)

e13054 Background: Cetuximab, a chimeric mouse-human IgG monoclonal antibody against EGFR, has a ~3% hypersensitivity reaction rate, but rates are regional (~1% in New England, up to 22% in Tennessee). A study from the NEJM showed most severe hypersensitivity reactions were associated with high pre-treatment IgE antibodies against galactose-α-1,3-galactose. In this study, we retrospectively defined our rate of hypersensitivity reactions, and prospectively studied IgE and IgG levels. Methods: IRB approval was obtained for prospective serum collection and five-year retrospective review (2006-2010) conducted at a single academic medical center. For the prospective trial, all patients signed informed consent. Serum was collected pre- and post-treatment and analyzed for IgE and IgG serum levels. Abstracted data for both parts of the study included demographics, reactions to cetuximab, cancer history, laboratory values, blood type, and total cycles delivered. Results: To date, 8 of 20 planned patients were accrued to the prospective trial. Two patients (25%) experienced grade 3 anaphylaxis; both had detectable (>0.35 IU/ml) pre-treatment IgE levels, compared with non-reactors (IgE levels undetectable). There were no changes in IgE or IgG levels during treatment. For the retrospective study, 47 patients (27 men) received a total of 358 cycles of cetuximab. There were 17 colorectal, 18 head/neck, 8 gynecologic, and four other malignancies (26 squamous cell-, 21 adeno-carcinomas. Seven patients (15%) experienced a reaction preventing subsequent infusion, including four grade 3 and two grade 4 anaphylaxis, and one grade 2 infusion-related reaction. Only one patient with colorectal cancer had a reaction (5%), yet 5 of 18 head and neck cancer patients (28%) and two of eight gynecologic cancer patients (25%) did. Six of the 7 patients with severe reactions had squamous cell cancers. Conclusions: Baseline elevated IgE levels predicted immediate hypersensitivity reactions to cetuximab. Reactions disproportionately affected patients with squamous cell cancers. Our rate of hypersensitivity reactions (15%) support other data showing that the mid-Atlantic U.S. states have a higher rate. Prospective data continues to be collected.
Survival benefits among patients with end-stage renal disease receiving dialysis versus no dialysis.
Authors: Ibrahim Nayef Dahbour, Maen Abdelrahim, Valda D Page, Shouhao Zhou, Chan Shen, Sriram Yennu, Bo Zhao, Joanna-Grace Mayo Manzano, Marina Ciny George, Joseph L. Nates, Alvin Howard Moss, Rima Pai, Ala Abudayyeh
Journal: Journal of Clinical Oncology (2016)

55 Background: Retrospective study of the outcomes of Stage IV Cancer Patients with End Stage Renal disease Receiving Dialysis and comparing the survival benefits among the patients who received Hemodialysis versus who didn’t at a Comprehensive Cancer Center. Methods: Retrospectively review all patients admitted to MDACC from 2005-2014 and diagnosed with stage IV solid tumor admitted with Acute kidney injury and a nephrology consult were included (N = 903) 19.82% received dialysis (n = 179) versus 80.17% did not receive dialysis (n = 724). The main endpoints of the study to be evaluated would be survival &amp; hospital death. Results: Kaplan-Meier overall survival curve of the dialysis group vs the non-dialysis p-value &lt; 0.001 indicating that patients who underwent dialysis had a poorer overall survival. This was further explored in a multivariate model where at any given time; a patient who underwent a dialysis is 1.318 times as likely to experience a death as a patient who did not undergo a dialysis with the same other clinical factors. The association between dialysis and death in hospital was explored using multivariate model indicated dialysis (odds ratio = 3.339, 95% CI (2.212, 5.04), p &lt; 0.001, ICU (odds ratio = 2.624, 95% CI (1.905, 3.613), p &lt; 0.001), and a lower serum albumin level (p &lt; 0.001) are factors associated with a higher probability of death in hospital. Matched sample where evaluated using propensity score matching &amp; Weighting and the dialysis group still shows a significant negative effect on Overall Survival with (p = 0.003). ICU patients Subset Analysis &amp; SOFA Score: 49.9% had ICU visits in our database with SOFA scores (37.9% were dialyzed). Using propensity score weighting method, the estimated hazard rate is 0.892 with 95% CI (0.775, 1.027) and p = 0.113, showing NO evidence that dialysis is a prognostic factor for ICU patients after controlling SOFA score. In the ICU cohort, the median survival time for dialysis 18 days (95% CI: 14-23) and no dialysis 19 days (95% CI: 15-25). Conclusions: We can conclude that Dialysis when offered to advanced cancer patients does not improve mortality. Creating a hemodialysis prognostic tool relevant to cancer population would be of great benefit to Nephrologists, Oncologist and patients.