tbuckley/cabot-search huggingface dataset:
A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias
Authors: D. J. Deangelo, R. M. Stone, L. B. Silverman, W. Stock, E. C. Attar, I. Fearen, A. Dallob, C. Matthews, J. Stone, S. J. Freedman, J. Aster
Journal: Journal of Clinical Oncology (2006)

6585 Background: Functional screening of T-ALL cell lines for sensitivity to NOTCH inhibitors has led to the discovery of frequent NOTCH1 gain-of-function mutations in the majority of human T-ALL. Gamma secretase catalyzes the cleavage of the Notch receptor within the transmembrane domain thereby releasing the Notch intracellular domain, which translocates to the nucleus to activate transcription of target genes. Gamma secretase inhibitors can induce G 0 /G 1 arrest, decrease cell viability, and cause apoptosis of T-ALL cell lines carrying Notch activating mutations. MK-0752 is a potent gamma secretase inhibitor in clinical development (IC 50 ∼50 nM). Methods: Patients with relapsed T-ALL and other leukemias were enrolled using an accelerated dose escalation scheme with 1 patient/dose level until ≥ grade 2 toxicity, followed by 3–6 patients/level. MK-0752 was administered by once-daily oral dosing in 28 day cycles. DLT was grade 3 or 4 non-hematologic toxicity during cycle 1. Plasma pharmacokinetic (PK) profiles and Abeta 40 peptide levels were measured. Results: Six adult and two pediatric patients with leukemia (seven with T-ALL and one with AML) received MK-0752 dosed at 150, 225, and 300 mg/m 2 . Treatment duration ranged from 2 days to 56 days before patients discontinued for disease progression or drug-related toxicity. Dose-limiting toxicity (DLT) was Grade 3/4 diarrhea at 300 mg/m 2 . Four of the seven T-ALL patients had Notch activating mutations. One patient with T-ALL and a Notch activating mutation treated with 150 mg/m 2 (300 mg) daily achieved a 45% reduction in a mediastinal mass at the end of 28 days as best response, but subsequently progressed by 56 days. Mean PK parameters at 150, 225, and 300 mg/m 2 on Day 1 were AUC 0–24hr = 723, 754, 1592 μM·hr, C max = 55, 40, 121 μM, C 24hr = 18, 28, 59 μM, and t max = 1, 8, 9 hr. Measurements of gamma secretase inhibition showed a 24–69% decrease in plasma Abeta 40 peptide levels on Day 14 compared to predose. Conclusions: MK-0752 was well-tolerated in a limited number of patients below 300 mg/m 2 , and further enrollment is underway to establish the MTD. Plasma concentrations of MK-0752 at all doses were sufficient to inhibit gamma secretase. Leukemia samples will be assessed for Notch inhibition. [Table: see text]
ERCC1 mRNA levels as a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.
Authors: Shuichiro Uemura, Hidekazu Kuramochi, Go Nakajima, Yasuto Sato, Ryota Higuchi, Masakazu Yamamoto
Journal: Journal of Clinical Oncology (2014)

239 Background: To date, no prognostic biomarker for biliary tract carcinoma has been identified. In previous studies of biliary tract carcinoma, no reliable data was found due to the varying composition of the cancer type (gallbladder, cholangiocarcinoma, and ampullary carcinoma), differences in tumor location, a mixture of curative and non-curative operations, and differences in operative methods. Methods: Fifty extrahepatic cholangiocarcinoma patients who underwent a pancreatoduodenectomy with R0 resection at the Tokyo Women’s Medical University Hospital were examined. All patients were pathologically diagnosed as having papillary or tubular adenocarcinoma. T-RNA was extracted from FFPE samples, and mRNA expression levels were measured by real-time RT-PCR. Results: In the preliminary analysis, 10 patients who have survived more than 5 years (LS group) and 10 patients who had a relapse within 2 years (SS group) were selected. EGFR, AREG, EREG, MMP-9, CDH-1, PARP1, and ERCC1 mRNA expression were examined; only the ERCC1 mRNA levels showed a significant difference between the LS and SS groups (median ERCC1: LS 26.5 vs. SS 9.7, p=0.0073). The median survival time (MST) of the patients with high ERCC1 levels was significantly higher than that in patients with a low ERCC1 level (MST: not reached vs. 16M). Then, 30 more patients with the same backgrounds were added to the study, and ERCC1 mRNA levels were measured in all 50 patients. The patients with high ERCC1 mRNA levels had a significantly greater overall survival rate compared with those with low ERCC1 levels (MST: not reached vs. 12.5M, 5-year survival rate: 92% vs 51%; p=0.04). In multivariate analysis, no lymph node metastases or high ERCC1 expression were significantly associated with better overall survival. Conclusions: ERCC1 mRNA expression seemed to be a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.
Evaluation of vinorelbine (N) and trastuzumab (H) as first-line therapy for patients (pts) with HER2- positive metastatic breast cancer (HER2+ MBC): Impact on clinical response and cardiac function
Authors: V. Guillem Porta, M. Martin, M. Gil Gil, P. Kellokumpu-Lehtinen, F. Majois, J. Gasmi, D. Aubert, O. Bourrillon
Journal: Journal of Clinical Oncology (2004)

636 Background: Combination therapy of vinorelbine (N) and trastuzumab (H) has recently been shown to be an active and safe regimen for HER2 positive MBC patients (Burstein JCO 01, 19;2722–2730). Here we report results of a multinational phase II trial. Methods: HER2 positive MBC pts (IHC 3+ or FISH + by centralised testing), with measurable disease, KPS = 70%, no prior H or N were treated with N : 30mg/m2/week and H: 4 mg/kg on day1 as loading dose and then 2mg/kg /w. Patients were reassessed every 8 w. All pts were evaluated for the left ventricular ejection fraction (LVEF) at the baseline and every 6 months and more often if needed. Either ultrasonography or MUGA scan were used. Results: Between October 2000 and June 2002, 69 patients were included in the study, median age: 53 years (30–74), prior neo/adjuvant chemotherapy: 65.2%, prior hormonal therapy: 49.3%, visceral metastasis: 75.4%. Sixty-six patients were evaluable for response and 68 pts for toxicity. The overall response rate was 61%, disease control (CR+PR+SD = 24 weeks) was 79%. The median duration of response was 11.7 months, and median progression-free survival was 10 months. Median survival has not yet been reached. The regimen was well tolerated, WHO grade 3–4 neutropenia (44.6% of cy) with 2 episodes of febrile neuropenia, H infusion reactions grade 3 (1.5 % of pts), grade 3: asthenia (8.8 % of pts), neuropathy (4 % of pts) and infection (6 % of pts). No severe nausea, vomiting or alopecia have been reported. The median LVEF at baseline was 64%. At week 28, forty-one of 68 pts (60 %) were rescreened for LVEF; the median LVEF was unchanged at 58%. Four pts experienced a decline of LVEF below 50%. This decline of LVEF was asymptomatic in 3 out of 4 pts and resolved after discontinuation of H for one cycle. Subsequently treatment was reintroduced for these 3 pts without further complications. One pt came off study due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Conclusion: Our results indicate that N + H is one of the most active treatment regimens for pts with HER2 positive MBC and demonstrates to be safe regimen. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche; Aventis; Lilly; Pierre Fabre
Phase I/II study of TH-302 in combination with pemetrexed in patients with solid tumors including NSCLC.
Authors: G. Vlahovic, J. R. Infante, A. C. Mita, A. M. Traynor, J. R. Molina, M. E. Lacouture, V. K. Langmuir, C. Eng, S. Kroll, M. J. Borad
Journal: Journal of Clinical Oncology (2010)

e13535 Background: TH-302 is a 2-nitroimidazole hypoxia-activated prodrug of the DNA alkylator, bromo-isophosphoramide mustard. In preclinical models, TH-302 was active alone and enhanced the activity of pemetrexed (Pem). A phase I/II study was conducted to establish the safety and tolerability, and investigate the activity of TH-302 in combination with Pem. Methods: This study used standard solid tumor eligibility criteria except patients (pts) could not have received prior Pem. Pts received IV TH-302 on Days 1 and 8 and Pem 500 mg/m2 on day 1 of a 21 day cycle. A standard 3+3 pts design was used with a TH-302 starting dose of 240 mg/m2. Following the determination of the MTD, a dose expansion component enrolled subjects with second-line NSCLC. The objectives of the study were to determine the MTD/RP2D of TH-302 with Pem, and to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy. Results: 29 pts [14M/15F, median age: 61y (range 22 to 86y), ECOG PS 0/1: 16/13] were enrolled at 5 sites and treated at TH-302 doses (mg/m2) of 240 (5 pts), 340 (7), 400 (1), 480 (9) and 575 (7). Primary tumor sites: 9 NSCLC, 4 colorectal, 3 pancreas, 3 HCC, 2 renal, 8 other sites. Treatment is ongoing in 7 pts; 16 pts discontinued prior to Cycle 6 (10 PD, 3 pt/physician decision, 2 clinical deterioration, 1 AE). DLTs were Gr 4 thrombocytopenia and Gr3 oral mucositis and oral candidiasis. Gr 3/4 neutropenia, thrombocytopenia and anemia occurred in 48%, 26% and 15% of pts. Skin and mucosal toxicities occurred in 18 (62%) and 20 (69%) pts, respectively, including four Gr 3 mucosal events (oral mucositis and oral candidiasis). Other common AEs were fatigue (50%) and nausea (46%). Based on DLTs and tolerability a TH-302 RP2D of 400 mg/m2 with Pem 500 mg/m2 was selected. There was no PK interaction between TH-302 and Pem. Best Response: 9 PRs (35%) and 9 SDs (35%) were reported in the 26 evaluable patients including 50% PR and 38% SD in 8 evaluable patients with relapsed/refractory NSCLC. Conclusions: TH-302 may be administered in combination with full dose Pem. Hematologic toxicity was greater than that seen with Pem alone. TH-302-related skin and mucosal toxicities were dose limiting but reversible. Encouraging antitumor activity has been observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Threshold Pharmaceuticals, Inc. Threshold Pharmaceuticals, Inc. Threshold Pharmaceuticals, Inc. Threshold Pharmaceuticals, Inc.
Spanish Lung Adenocarcinoma Trial (SLAT) of customized treatment based on EGFR mutations (mut) and BRCA1 mRNA expression: Ancillary analyses of Abraxas and RAP80 expression
Authors: R. Rosell, M. Provencio, M. Dómine, A. Pradas, F. Salazar, N. Reguart, M. Sala, P. Diz, I. Barneto, M. Tarón
Journal: Journal of Clinical Oncology (2008)

8037 Background: We carried out a study in metastatic NSCLC where treatment was customized according to EGFR mut status and BRCA1 mRNA levels. Loss of BRCA1 function increases sensitivity to cisplatin and resistance to antimicrotubule drugs (Quinn et al. Cancer Res 2003). The Abraxas-RAP80 complex can modulate BRCA1 function (Wang et al. Science 2007). A gene signature including BRCA1 predicts poor survival (Deeb et al. Cancer Res 2007). Methods: 93 patients (p) with lung adenocarcinoma or large-cell carcinoma were screened for EGFR Δ746–750 deletion and L858R mut and BRCA1 mRNA expression. 15 p with EGFR mut received erlotinib; 78 p without mut received chemotherapy according to BRCA1 levels (low: gemcitabine/cisplatin; intermediate: docetaxel/cisplatin; high: docetaxel alone). In addition, Abraxas and RAP80 mRNA expression were examined in 60/78 p without mut. Results: With a median follow-up of 10 months (m) for all 92 p, median survival (MS) has not been reached in 15 p with EGFR mut. MS has not been reached in 32 p with low BRCA1 levels; MS is 9 m in 34 p with intermediate BRCA1 levels and 11 m in 12 p with high BRCA1 levels (P=0.03). For the 60 p in whom Abraxas and RAP80 were analyzed, MS has not been reached in p with intermediate levels of all 3 genes; MS is 6 m in p with low or high levels of all 3 genes and 11 m in other p. In the multivariate analysis of survival (table), BRCA1 expression emerged as a significant prognostic marker (hazard ratio [HR] for p with intermediate levels, 4.8 [P=0.02]; HR for p with high levels, 13.4 [P=0.004]). Conclusions: Low levels of BRCA1 indicate a favourable outcome to chemotherapy, and BRCA1 may be both a prognostic and predictive biomarker. The assessment of Abraxas, RAP80 and BRCA1 expression can help to further refine customized chemotherapy. Hazard Ratio 95% CI P ECOG PS 0 1 (ref.) 1 1.8 0.3–11.2 0.49 2 1.7 0.2–18.2 0.63 RAP80 mRNA levels < 0.71 1 (ref.) 0.71–1.36 0.08 0.01–0.48 0.005 > 1.36 0.20 0.04- 0.88 0.03 BRCA1 mRNA levels (terciles) < 4.44 1 (ref.) 4.44–10.9 4.8 1.29–17.84 0.02 > 10.9 13.4 2.34–77.46 0.004 No significant financial relationships to disclose.
Phase II trial of bevacizumab and everolimus in the treatment of patients with metastatic melanoma: Preliminary results
Authors: J. D. Peyton, D. R. Spigel, H. A. Burris, C. Lane, M. Rubin, M. Browning, D. Trent, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2009)

9027 Background: Metastatic melanoma remains resistant to therapy. Anti-angiogenesis agents and m-TOR inhibitors have shown modest activity as single agents. In this multicenter phase II trial, we evaluated the combination of bevacizumab and everolimus in the treatment of patients with metastatic melanoma. Methods: Patients with unresectable metastatic melanoma with ECOG PS 0–2 were eligible. Up to 2 previous treatment regimens were allowed; patients previously treated with angiogenesis or m-TOR inhibitors were excluded. Additional eligibility requirements: adequate organ function, no CNS involvement, standard bevacizumab exclusions. All patients received bevacizumab 15mg/kg IV q 3 weeks, and everolimus 10mg po daily. Patients were evaluated every 6 weeks, and treatment continued until disease progression. Results: Between February 2008 and October 2008, 56 patients were enrolled; the first 31 patients are included in this interim report. The median age was 71 years (range 36 to 89 years); 19 patients (61%) had visceral metastases; 0/1/2 previous regimens, 12/11/8 patients; ECOG PS 0/1/2, 17/11/1. 28 patients (90%) received at least 6 weeks of treatment; 3 patients withdrew prior to 6 weeks (toxicity, 2 patients; intercurrent illness, 1 patient). 1 of 28 evaluable patients (4%) had a PR. However, 19 additional patients (68%) had stable disease (15 of these patients had measurable decrease in tumor size), for a disease control rate of 72%. 14 patients remain on treatment, after treatment durations of 2 - 7.5 months. After a median followup of 5 months, the median progression-free survival is 3.5 months (95% CI 2.4 - 5.4 months). Bevacizumab/everolimus was generally well tolerated. 1 patient withdrew because of interstitial pneumonitis (reversible) and 1 patient had a fatal MI, possibly bevacizumab-related. Grade 3 mucositis occurred in 13%; other grade 3 toxicities occurred in &lt; 10% of patients. Conclusions: The combination of bevacizumab and everolimus was well tolerated and has activity in patients with metastatic melanoma. Updated results in all 56 patients will be presented. [Table: see text]
Abstract 11542: Relationship between Neurologically Intact Survival after Return of Spontaneous Circulation (ROSC) from Out-of-Hospital Cardiac Arrest and Time Interval from Collapse to ROSC
Authors: Ken Nagao, Eizo Tachibana, Kei Nishikawa, Naohiro Yonemoto, Morimasa Takayama, Hiroshi Nonogi, Shinichi Shirai, Takeshi Kimura
Journal: Circulation (2012)

BACKGROUND Although early achievement of ROSC is critical to neurologically intact survival from cardiac arrest, few data are available in any cardiac arrest rhythm. METHODS From the data of the Al...
Interim analysis of the multicenter phase II HEDON trial evaluating pathological response to pre-operative docetaxel and docetaxel+trastuzumab (T) in locally advanced breast cancer (BR) stratified by HER2-status
Authors: S. Paepke, M. Kiechle, D. Paepke, E. Klein, M. Warm, D. Augustin, O. Camara, J. Nährig, R. Kates, N. Harbeck
Journal: Journal of Clinical Oncology (2009)

e11512 Background: Docetaxel is the most effective mono-substance in metastatic BC and highly effective in adjuvant chemotherapy. Early docetaxel-monotherapy data in primary systemic therapy (PST) showed a pCR of 18% (Amat et al; 2003), comparable with pCR-rates of standard PST combination chemotherapy. HEDON was conducted to evaluate efficacy of docetaxel ± T with regard to pCR (defined as absence of invasive and non-invasive BC in breast and lymph nodes) as primary endpoint; secondary endpoints were safety, breast conservation rate and 5-yr DFS. Additionally Trans-HEDON includes a translational research program to identify molecular RNA and methylation (DNA) based markers of response to docetaxel-monotherapy. Methods: From 2006 until 2008, the multicenter phase II HEDON trial fully recruited 93 pts, with therapy still ongoing; tumor stages: T2 (23), T3 (11), T4 (5); nodal status: N0 (16), N1–2 (23). Arm A: Docetaxel (100 mg/m 2 x6) in HER2-negative (n=60) and Arm B: Docetaxel (100 mg/m 2 x6) in combination with T (18x2mg/kg KG) preoperatively in HER2-overexpressed BC (n=33), followed by surgery and then by adjuvant epirubicin/cyclophosphamide (E90Cx4), radiotherapy if indicated, T for altogether one year, and endocrine therapy in ER+ and/or PgR+ BC. Pre-planned interim analysis (safety and efficacy) was performed after recruitment of 39 pts (Arm A 26, Arm B 13). Results: In Arm A, 7 pts. (26.9%) achieved pCR and 9 pts. (34.6%) pPR. In Arm B, 7 pts. (53.8%) achieved pCR and all 6 others (46.2%) pPR. Neutropenia occurred in 11 pts. (8 with grade 3). Moderate (25%) dose reduction was necessary in 13 pts., and 50% dose reduction in one patient. Conclusion: According to interim analysis of the HEDON trial, docetaxel-monotherapy of 6 cycles at 100mg/m2 q21 (plus T in HER2-positive BC) is an effective and safely administrable PST. There were no unexpected toxicities, and preliminary pCR rates in HER2-neg (26.9%) and HER2-pos (53.8%) pts. were comparable to those of combination chemotherapy. These interim results will be completed by final analysis on the full collective, with molecular predictors from TransHEDON hopefully identifying patients who derive extensive benefit. [Table: see text]
A phase II clinical and biological study of lithium carbonate (Li) in patients with low-grade neuroendocrine tumors
Authors: S. J. Lubner, H. Chen, K. Holen, N. LoConte, L. Rikkers, S. Weber, T. Warner, J. Eickhoff, T. Fass, W. Schelman
Journal: Journal of Clinical Oncology (2009)

e15662 Background: Low-grade neuroendocrine tumors (NETs), such as carcinoid, islet cell tumors, and medullary thyroid carcinomas, respond poorly to chemotherapy, and effective, less toxic therapies are needed. Glycogen Synthase Kinase (GSK)-3β, a multifunctional protein kinase, has been shown to regulate growth and hormone production in NETs. Use of lithium carbonate (Li) in murine models suppressed carcinoid cell growth, reduced GSK-3β levels and reduced expression of chromogranin A. This study assessed the efficacy of Li in patients with NETs. Methods: Eligible pts had pathologically-proven, measurable low-grade NETs. Prior treatment was allowed if completed &gt;4wks prior to registration. Standard eligibility criteria were used, and use of medications affecting Li metabolism or levels were prohibited. A single-arm, open-label, two-stage Phase II design was used. Li was dosed at 300mg orally TID with meals, titrated to a target serum level of 0.8–1.0mmol/L. The primary endpoint was objective tumor response by RECIST. Secondary endpoints included overall survival, progression-free survival, decrease of serum tumor markers, toxicity, and quality of life. Results: 15 pts were enrolled between 10/3/07and 7/17/08; 6 men, 9 women. The median age was 58 (range 47–74). Patients’ diagnoses were carcinoid tumor for 8 subjects, islet cell tumor for 5 subjects, and 2 unknown primary sites. ECOG PS was 0 (6 patients) or 1 (9 patients). Two pts came off study due to side effects (tremor, dizziness/abdominal pain). There were no radiographic responses. Due to an early stopping rule requiring at least 1 objective response in the first 13 evaluable pts, the study was closed to further accrual. 13 patients had pre- and post-therapy biopsies. Evaluation of quality of life and GSK-3β levels in tumor tissue is ongoing. Conclusions: Li was ineffective at obtaining a radiographic response in our 13 evaluable patients who were treated as part of this study. We will determine from tumor biopsies whether Li was effective at phosphorylating GSK-3β in order to make conclusions about GSK-3β as a therapeutic target for future NET treatment strategies. Funded through NIH grant R21CA117117- 01A2 and CTRC grant 1ULRR025011. No significant financial relationships to disclose.
Hydralazine-demethylating systemic therapy for breast cancer
Authors: A. M. Safar, S. Macleod, V. Klimberg, R. Henry-Tillman, C. Fan, L. Hutchins, I. Makhoul
Journal: Journal of Clinical Oncology (2006)

13131 Background: Cancer results from accumulation of gene deregulations. DNA sequence alterations are of unquestioned importance in this process, but are not exclusive. Alterations in gene function unaccounted for by DNA sequence changes (Epigenetic) are quite common, and seem to contribute to carcinogenesis. Abnormal methylation at the promoter region of Tumor Suppressor Genes results in gene transcriptional silencing, and is wide spread in many cancers, including Breast Cancer (BC). Alterations in cancer DNA methylation (DNAm) is among the best characterized epigenetic anomalies. An attractive feature of DNAm is its predisposition to pharmacologic reversal as a therapeutic intervention. Here, we used the cardiovascular drug hydralazine (H) to confirm its proposed demethylating effects and to examine its safety in clinically recommended doses concurrent with chemotherapy. Methods: Operable BC patients undergoing neoadjuvant therapy were enrolled on this study (n = 13). We examined DNAm levels at 2 time points; untreated tumor (biopsy) and H-treated specimen (resection) from the same patient. Global DNAm levels were estimated by examining the methylation level in Alu repeats. The study design conformed to a phase I, dose escalating scheme. H was administered at 50 mg orally TID for the first cohort in addition to standard chemotherapy. Results: H was well tolerated to a maximal dose of 200 mg QID. 1 patient discontinued the drug for headache. 4 patients completed treatment (approx. 4 months) and underwent surgical resection and assessment of methylation. Global Demethylation (defined as decrease of Alu methylation level by ≥5%) was observed in 2/4 [−8% and −9%, respectively]. The remaining patients have undergone surgery but DNA testing not performed as yet (results will be presented in the meeting). Conclusions: Hydralazine is well tolerated in normotensive individuals, in doses ≤ 200 mg/d concurrently with standard chemotherapy for breast cancer. Further, hydralazine produces decrement in DNAm of clinical cancer specimens. Effect of this demethylation on the expression of biologically important genes such as ER and p16 will be evaluated and presented once available. The biologic effect of such alteration in genomic DNAm would require subsequent investigation to prove its therapeutic impact. No significant financial relationships to disclose.
Abstract 14502: Variability in Traditional and Novel Cardiovascular Risk Factors by Ethnic Origin: Insights from the Primary Care Audit of Global Risk Management (PARADIGM) Study
Authors: Aanika Gupta, Mahesh Kajil, Narendra Singh, Michelle Tsigoulis, Subodh Verma, Milan Gupta
Journal: Circulation (2012)

Background: Coronary heart disease is a primary public health concern both in North America and globally. Several studies have demonstrated that persons of South Asian origin (those originating fro...