tbuckley/cabot-search huggingface dataset:
A phase I trial of fixed-dose-rate (FDR) gemcitabine and irinotecan combination in patients with advanced pancreatic and biliary cancer
Authors: W. Sun, M. E. Theobald, D. Hershock, D. G. Haller
Journal: Journal of Clinical Oncology (2004)

4112 Background: It has seen suggested that the FDR infusion of gemcitabine increases intracellular triphosphate gemcitabine, which in turn may achieve a higher treatment benefit compared to the standard infusion. Combination gemcitabine and irinotecan may have additive or synergistic effects with few or no overlapping toxicities. Methods: A open-label phase I dose escalation trial is designed to evaluate the safety of combination FDR infusion gemcitabine and irinotecan in advanced/metastatic pancreatic and biliary cancer. The primary end points are to find the dose for phase II study, dose limiting toxicity (DLT), and maximum tolerable dose (MTD). The response of the combination will also be determined for patients with measurable or evaluable diseases. Gemcitabine is infused intravenously at a FDR of 10 mg/m2/min, and the infusion time is based on the dose level. Irinotecan is administered intravenously over 60 min after gemcitabine. Both gemcitabine and irinotecan are given on day 1 & 8 of a 21-day cycle. The dose-escalation schedule is listed in table 1. Results: Nineteen pts have been entered to date (median age 60, [23–73], mean PS 1). No DLT was observed in 3 pts enrolled at dose level 1. 1 of 7 pts developed DLT (Gr 4 neutropenia & Gr 3 thrombocytopenia) at dose level 2. 1 of 8 pts experienced dose-limiting Gr 4 neutropenia at dose level 3. Non-hematologic toxicities are mild to moderate, including Gr 1–2 nausea/vomiting, diarrhea and fatigue. 2 patients developed DVT during the treatment. Of 17 evaluable pts, there have been 4 partial responses (PR), and 9 pts have maintained stable disease (SD) (8 of these 9 pts have had ≥ 6 cycles of treatment). 2 pts with advanced pancreatic cancer, after 22 cycles of the combination chemotherapy, are still on therapy. Conclusions: The study is on-going at dose level 4. No MTD has been reached. The combination is tolerable and encouraging Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer
Randomized phase II trial of cisplatin/gemcitabine with or without LY293111, a multiple eicosonaid pathway modulator, in patients with chemotherapy naïve advanced non-small cell lung carcinoma
Authors: P. A. Janne, L. Paz-Ares Rodriguez, M. Gottfried, M. N. Reaume, T. Kaukel, Y. W. Oh, A. Sykes, N. Enas, L. H. Brail, J. Von Pawel
Journal: Journal of Clinical Oncology (2006)

7024 Background: The eicosanoid pathway is altered in NSCLC. Pharmacological activators of peroxisome proliferator-activated receptor-gamma (PPARγ) have been shown to inhibit lung tumors in vitro. LY293111 inhibits the eicosanoid pathway, is a PPARγ agonist and modulates adipophilin and adiponectin expression levels in vitro. LY293111 is well tolerated and can be administered with cisplatin/gemcitabine. A randomized phase II study in NSCLC was undertaken. Methods: Pts with stage IIIB/IV NSCLC were randomized to two doses of LY293111 (200 mg BID (Arm A) or 600 mg BID (Arm B) or placebo (Arm C) alone for 7 days followed by concurrent cisplatin (75 mg/m 2 ;d1) and gemcitabine (1250 mg/m 2 ;d1,8) q21 days. Treatment was continued until disease progression or toxicity. Primary endpoint was PFS with 75% power to detect 33% improvement compared to placebo (5 months). Calculated sample size was 65 pts/arm (195 total) with a one sided type I error of 0.2. Changes in adipophilin mRNA expression and adiponectin serum levels were assessed at baseline and day 7. Results: Between 09/03 and 07/04, 201 pts were randomized and 195 treated. Demographics (all pts): M:F (65%:35%); median age 61 (range 27–87); stage IIIB/IV (15%:85%); ECOG PS (0:36%;1:64%). Demographics were well balanced between the 3 arms. Most common CTC grade 3/4 toxicities were nausea (8%), vomiting (7%), fatigue (6%) and diarrhea (6%) with only diarrhea related to dose of LY293111 (p=0.03). Response rates (CR+PR) were similar in all 3 arms (A:20%; B:27%; C:21%). There was no significant difference in median PFS (95% CI) between the arms (A: 4.6 months (3.2–5.0); B:6.0 months (4.6–7.2); C:6.0 months (5.2–7.0)). Median survival (95% CI) was similar in all 3 arms (A: 7.3 months (6.2–9.4); B:7.9 months (7.2–9.7); C: 9.0 months (7.7–12.5). Median change in serum adiponectin levels at d7 were significantly higher in arm B vs. placebo (p &lt; 0.05). Adipophilin expression at d7 was increased in a dose dependent manner (p=NS) in arms A and B vs. placebo. Conclusions: LY293111 in combination with cisplatin/gemcitabine did not increase median PFS compared to placebo in pts with NSCLC. Pharmacodynamic modulation was observed but did not impact efficacy. [Table: see text]
Multicentre phase II trial of combination neoadjuvant hormone therapy and weekly docetaxel prior to radical prostatectomy in high risk localized prostate cancer (CUOG-P01a)
Authors: M. E. Gleave, K. N. Chi, L. Goldenberg, J. Chin, E. Winquist, L. Klotz, F. Saad, J. Trachtenberg
Journal: Journal of Clinical Oncology (2004)

4635 Background: Docetaxel is active for hormone refractory prostate cancer (HRPC) and may have additive effects if combined with androgen ablation in hormone naïve disease. Potential beneficial or adverse effects of combination vs sequential chemo-hormonal regimens are poorly defined. The objective of this trial was to assess the tolerability and pathologic effects (including high-throughput transcriptional and immunohistochemical bioprofiling) of 6 months of combined androgen ablation + docetaxel in men with high risk localized prostate cancer prior to radical prostatectomy. Methods: In a Phase II multicentre, single arm, open-label study men with newly diagnosed previously untreated clinically localized high-risk disease received androgen ablation (buserelin acetate 6.3 mg q 8 weeks x 3, + anti-androgen for 4 weeks) + weekly docetaxel (35 mg/m2 iv weekly x 6 q 8 weeks for 3 cycles). Results: 72 men with a mean age of 55 years (range 45–74) and mean serum PSA of 17.8 μg/L (range 2.5–66) were enrolled at 6 sites across Canada. Baseline prognostic factors included 51% cT2 and 38% cT3; 32% Gleason 7, 32% Gleason 8, and 27% Gleason 9; PSA <10 in 44%, 10–20 μg/L in 25%, and >20 μg/L in 31%. Eight patients discontinued study therapy for > grade 3 toxicity (n=5), withdrawal of consent (n=1), or identification of metastatic disease (n=2). 64 patients completed protocol therapy and surgery. 38 (59%) were pathological T2N0, including 2 complete responders (P-0) and 10 with residual microfoci of cancer. 26 (41%) were pT3, including 7 with seminal vesicle invasion (pT3c), and 4 T3N1. Positive surgical margins were identified in 17 (27%), including 5 pT2 and 12 pT3 tumors. Conclusion: Combined androgen ablation + weekly docetaxel is reasonably well tolerated and results in significant pathologic responses and lower than expected positive surgical margins for this high-risk group. Tissue microarray construction and transcriptional profiling are underway to define treatment-induced changes in gene expression. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Novartis; OncoGenex Abbott; Avenits; Novartis Aventis
A pharmacokinetic (PK) and safety study of sorafenib plus capecitabine in advanced solid tumors
Authors: C. E. McKay, J. Infante, S. Jones, J. Bendell, F. A. Greco, T. M. Markus, D. R. Spigel, D. A. Yardley, J. Woudenberg, C. D. Lathia, H. A. Burris
Journal: Journal of Clinical Oncology (2009)

e14548 Background: The addition of a multi-targeted kinase inhibitor such as sorafenib (S) to standard chemotherapy holds promise for improving therapeutic efficacy in multiple advanced solid tumors. This study is designed to evaluate the PK and overall safety of S in combination with capecitabine (C). Methods: Eligibility included patients (pts) with refractory solid tumors, 0–1 ECOG, adequate organ function, and no prior anti-VEGF tyrosine kinase inhibitors. This single institution study enrolled two simultaneous cohorts of 6 pts each followed by an expansion: Cohort A received S 400 mg bid for 21 days and C 750 mg/m 2 bid for 14 days of a 21-day cycle. Cohort B received S 400 mg bid for 21 days and C 1,000 mg/m 2 bid for 14 days of a 21-day cycle. Intensive PK collections (pre, 30 min, 1, 2, 4, 6, 8, and 12 hr) were obtained following a week of exposure to S alone, C alone (both C and 5FU levels measured), and both S and C in combination. Results: 17 pts dosed since 2/1/08: median age 66 years (range 36–87); ECOG 0 14(82%); and white 15(88%). Tumor types include colon (4), pancreas (2), prostate (2), and other (11). No treatment-related deaths occurred. Target toxicities are outlined in table below. Despite early and aggressive clinical management, hand foot skin reaction (HFS) necessitated dose reductions in 1 pt in cohort A and 4 pts in cohort B. In total, only 1(14%) pt in cohort A required a dose reduction, as opposed to 5(63%) pts in cohort B. The median # of cycles was 2 (range 1–10), and 5 pts (29%) remain on study. Of the 13 pts evaluable for response, 8 (47%) had stable disease following first restaging scans. PK samples are being analyzed to compare Cohort A vs. B. Conclusions: The results of this trial will help guide future trials of S plus C. The 1,000 mg/m 2 bid dose of C in combination with full dose S required frequent dose modifications in our pt population secondary to overlapping toxicity (primarily HFS). Alternate schedules should be considered. PK analysis will be presented. [Table: see text] [Table: see text]
Abstract 17572: Regulation of Myocardial Collagen Synthesis and Degradation by Beta-Arrestin 1/2 in Maladaptive Ventricular Remodeling
Authors: Jinju Li, Tiju Theccanat, Shahab A Akhter
Journal: Circulation (2012)

Cardiac fibroblasts (CF) produce and degrade extracellular matrix and are critical in regulating myocardial remodeling which can lead to heart failure. β-arrestins regulate G protein-coupled recept...
Genomic predictors of pathologic response to preoperative chemotherapy for triple-negative and ER-positive/HER2-negative breast cancers
Authors: C. Hatzis, W. F. Symmans, F. Lin, B. Zheng, K. Yan, D. J. Booser, Y. Gong, V. Valero, G. N. Hortobagyi, L. Pusztai
Journal: Journal of Clinical Oncology (2008)

571 Background: First generation genomic predictors were derived from a mixture of different molecular subtypes of breast cancer and often aimed to predict pathologic complete response (pCR) to chemotherapy. Here we develop distinct predictors for clinically relevant molecular/phenotypic subtypes of breast cancer including (i) ER-/HER2-negative and (ii) ER-positive/HER2-negative tumors. We defined pCR or minimal residual cancer burden (RCB-I) as the desirable treatment response since they are associated with equally good long term survival. Methods: Affymetrix U133A profiles from 229 HER2-negative, stage I-III breast cancers were used to develop predictors separately for ER-negative (n=97) and ER-positive (n=132) cases. All patients received sequential paclitaxel, 5-fluorouracil, doxorubicin, cyclophosphamide (T/FAC) neoadjuvant chemotherapy. The combined pCR/RCB-I response rates were 47% in the ER-/HER2-negative and 17% in the ER-positive/HER2-negative cohorts. We used a penalized multivariate ROC (receiver operating characteristic) maximization algorithm to develop multi-gene predictors. Performance was estimated through complete 3-fold cross validation in each cohort and also across molecular subtypes to estimate phenotype specificity. Results: The ER-/HER-negative predictor included 116 probes and had 78% sensitivity, 77% specificity and 78% positive (PPV) and negative (NPV) predictive values and area under the ROC curve (AUC) of 0.85. The ER-positive/HER-negative predictor included 89 probes and had 64% sensitivity, 84% specificity, 44% PPVand 92% NPVand AUC of 0.84. When cross tested on the other clinical phenotypes the predictive values dropped dramatically. Prediction of excellent pathologic response (pCR/RCB- I) was significantly correlated with better distant relapse free survival for the entire study population (p<0.001). Conclusions: We developed molecular phenotype-specific predictors of excellent pathologic response to preoperative T/FAC chemotherapy. ER-negative/HER2-negative patients with a positive signature have 7 times greater probability and ER-positive/HER-negative cases have 5 times higher probability to achieve excellent response, respectively. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nuvera Biosciences Nuvera Biosciences Nuvera Biosciences
A double-blind, randomized, placebo-controlled phase II study of the steroidal aromatase inhibitor exemestane with and without the isoform selective histone deacetylase inhibitor (HDACi) entinostat in metastatic breast cancer (MBC).
Authors: D. A. Yardley, R. Ismail-Khan, J. F. Eakle, K. Miller, D. Paul, V. F. Borges, T. L. Helsten, J. F. Kroener, B. Melichar, K. H. Tkaczuk
Journal: Journal of Clinical Oncology (2010)

TPS128 Background: Anti-estrogentherapies, including aromatase inhibitors, are effective in the treatment of MBC patients who are estrogen receptor (ER) positive, but acquired resistance to these agents eventually develops in virtually all patients, leading to disease progression. Decreased ER expression levels and increase in growth factor signaling both contribute to resistance to aromatase inhibitors (Brodie et al 2009 J Steroid Biochem Mol Biol). Preclinically, HDACi reverse ER expression silencing (reviewed in Stearns et al 2007 Cancer Invest) and inhibit the growth factor signaling pathways that drive breast cancer growth (Huang et al 2009 Canc Res). Entinostat is an oral class 1 HDAC selective inhibitor that has been well tolerated to date and may be combined with aromatase inhibitors. The purpose of this ongoing clinical trial is to assess whether the addition of entinostat to the steroidal aromatase inhibitor exemestane can overcome and/or delay the acquired resistance to aromatase inhibitors in MBC. Methods: Post-menopausal females with ER+ MBC progressing on a non-steroidal aromatase inhibitor are eligible for this study. Target patient population consists of 80% of patients having measurable disease with 20% of patients having nonmeasurable disease only. 114 patients (pts) are planned to be randomized in a double-blind, placebo-controlled manner to either exemestane (25 mg QD) + entinostat (5 mg once weekly) or to exemestane (25 mg QD) + placebo. The study is designed to evaluate the hypothesis that the addition of entinostat to exemestane will increase the PFS by 2.3 months. (i.e. 3.7 months with exemestane versus 6 months with combination; 1-sided=10%, power= 80%). Correlative studies include analysis of changes in acetylation and gene expression in peripheral blood monocytes, and levels of circulating endothelial cells before and after initiation of treatment. The study is open in the United States, Hungary, Czech Republic, and Russia and current enrollment is 70% complete. No significant financial relationships to disclose.
Hint1 Deletion Impairs Liver Regeneration
Authors: Caroline Hora, Olivier Maurhofer, Monika Ledermann, Gisele Ferrand, Jean-Francois Dufour, Juliette Martin
Journal: Hepatology (2009)

Reference EPFL-CONF-159119View record in Web of Science Record created on 2010-11-30, modified on 2017-05-12
Pharmacokinetic–pharmacodynamic (PK-PD) modeling and simulation of serdemetan-induced QTc effects in a first-in-human study.
Authors: D. R. Huntjens, L. Van Beijsterveldt, S. Kraljevic
Journal: Journal of Clinical Oncology (2010)

e13011 Background: Serdemetan is a compound that can cause replicative stress type responses in tumor cells and it has been administered to patients with solid tumors. ECG data from an ongoing first-in-human study revealed effects on QT interval, related to serdemetan exposure. The aim of this project was to develop a PK-PD model to quantify the observed effects on QTc interval. Furthermore, model-based simulations were performed with different dosing scenarios to support the dose and regimen selection of next study cohorts. Methods: Clinical data from 36 subjects (doses from 4-300 mg QD) from the phase I study JNJ-26854165-CAN-1001 were used for PK and PKPD modeling. Plasma concentrations were used as input for the pharmacokinetic modeling. QTcF data were used as input for the PK-PD model. Modeling and simulations were performed using nonlinear mixed effect modeling in NONMEM version 6.2. Results: A two-compartment model with combined first- and zero-order absorption best described the pharmacokinetics of serdemetan after oral solution and tablet formulation. A small effect of food intake was observed on the absorption. QTcF effects over time were described by several components, including baseline QTc, heart rate correction (Fridericia's formulae), circadian rhythm, and the drug-induced effect, as described by a linear function of the plasma concentration. The developed PK-PD model was used to address the impact of different dosing schedules (QD, BID, Q2D) on the number of patients with a delta QTcF of > 60 ms. Simulations indicated that BID dosing had increased safety margin for QTcF effects, compared to QD or less frequent dosing at the proposed therapeutic range. Conclusions: PK-PD modeling enables the quantification of QTcF effects of serdemetan in a first-in-human study. Optimization of treatment schedules can be facilitated based upon simulation scenarios as proposed by the PK-PD model. PK-PD modeling in an early stage in drug development can be a valuable tool for dose and schedule selection. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson
Brief Communication: In Vivo Cortisone Sensitivity of Nonspecific Antitumor Activity of Corynebacterium parvum-Activated Mouse Peritoneal Macrophages2
Authors: Martin T. Scott
Journal: JNCI Journal of the National Cancer Institute (1975)

The nonspecific antitumor activity of Corynebacterium parvum-activated mouse peritoneal macrophages in vitro was inhibited by their prior treatment with cortisone acetate in vivo. Inhibition was marked (60%) 24 hours after cortisone injection and was still significant at 7 days, but antitumor activity was completely recovered by 9 days. This transient inhibition was sufficient to abolish the nonspecific protection afforded by C. parvum in an in vivo pretreatment model.
Staging evaluation with bone scan, liver ultrasound, and chest radiograph in patients with primary breast cancer: A systematic review.
Authors: Stuart-Allison Moffat Staley
Journal: Journal of Clinical Oncology (2012)

4 Background: Routinely, radiological investigation with bone scan, chest radiograph, and liver ultrasound are employed as baseline staging tests. The aim of this review was to examine indications for this costly routine screening, and, thus, we posed the following question: Among women with newly diagnosed breast cancer who are otherwise asymptomatic, does evaluation with bone scanning, liver ultrasound, and chest radiograph help to determine the extent of metastatic disease? Methods: We searched PubMed and EMBASE databases for relevant articles to find articles using detection rate, defined as the number of patients with an abnormal test result divided by the total number of patients tested, as the primary outcome of interest. In addition to detection rate, false-positive and false-negative rates are reported if provided in the study reports reviewed. In order to obtain overall estimates of detection rates in each test, the results from the studies were pooled and summed according to pathological stage. A 95% confidence interval was calculated for each of the pooled rates. Results: Eight articles out of 232 reviewed were included in the final analysis. The following pooled detection rates for bone scan were calculated according to stage: Stage I 7 of 544 (1.29%), Stage II 29 of 938 (3.09%), Stage I and II 36 of 1,482 (2.43%), and Stage III 39 of 312 (12.5%). For liver ultrasound: Stage I 1 of 213 (0.47%), Stage II 4 of 400 (1.00%), Stage I and II 5 of 613 (0.82%), and Stage III 6 of 143 (4.20%). And, for chest radiograph: Stage I 0 of 223, Stage II 2 of 473 (0.42%), Stage I and II 9 of 1,782 (0.51%), and Stage III 8 of 175 (4.57%). Conclusions: The routine use of bone scan, liver ultrasound, and chest radiograph in the staging evaluation of primary breast cancer patients is of little value in detecting metastatic disease in women with clinical stage I and stage II cancer, and therefore, should not be performed.
Participant characteristics on an international NCIC CTG breast cancer prevention trial
Authors: H. Richardson, D. Johnston, P. E. Goss
Journal: Journal of Clinical Oncology (2007)

1531 Background: Antagonizing estrogen with tamoxifen has set the precedent for preventing breast cancer. Aromatase inhibitors reduce contralateral breast cancer in the adjuvant setting more than tamoxifen. The goal of MAP.3 is to determine whether exemestane reduces invasive breast cancers in post-menopausal women at risk for the disease. Methods: NCIC CTG MAP.3 is a randomized placebo controlled double blind trial of exemestane versus placebo. Recruitment began in September 2004 in North America and Spain. Criteria for entry on MAP.3 include: a Gail score of 1.66%; previous benign breast disease including LCIS; age over 60. The target sample size for the trial is 4560. Baseline characteristics of women enrolled thus far on MAP.3 were reviewed to determine whether their projected risk of breast cancer is consistent with the assumptions made in designing the trial. Results: Baseline characteristics are available on the 1784 women enrolled to MAP.3 to date. Over 70% of participants are over 60 years old (mean 64; SD=8.2 years) and the majority of the women are Caucasian (85%). The average 5-year risk of breast cancer is 2.7% (median, 2.2%). However, a greater proportion of women over 60 (30%) have a substantially lower Gail score (&lt;1.66) compared to women less than 60 years of age (8%). Few women in the MAP.3 cohort have been enrolled on a basis of a history of prior breast atypical hyperplasia or LCIS (8%), or DCIS treated with mastectomy (2%). Nearly half the MAP.3 participants (45%) have at least one first degree relative with malignant breast cancer, and 7.5% of these women have 2 or more first degree relatives with the disease. Conclusions: The risk profile of the women on MAP.3 will determine the event rate and therefore the time to trial unblinding and analysis. This initial description of the MAP.3 population enrolled thus far indicates a slightly lower baseline breast cancer risk in comparison to the risk profile of those enrolled in previous breast cancer prevention trials with tamoxifen or raloxifene (NSABP P1, IBIS-1 and STAR). Reasons for this difference are being explored. [Table: see text]
Immunohistochemistry (IHC) analysis with 3 different antibodies (Abs) and thymidylate synthase (TS) evaluation of FISH-positive ALK-rearranged (ALK+) lung adenocarcinomas (ADK)
Authors: P. Bironzo, V. Monica, P. Graziano, L.A. Muscarella, L. Righi, S. Busso, C. Di Micco, A. Rimanti, A. Fulvi, L. Consito, F. Bertolini, A. Lombardi, G. Vincenzi, G. Rossi, S. Novello
Journal: Annals of Oncology (2015)