tbuckley/cabot-search huggingface dataset:
The first-in-human study of the solid oral dosage form of AZD6244 (ARRY-142886): A phase I trial in patients (pts) with advanced cancer
Authors: R. Agarwal, U. Banerji, D. R. Camidge, K. H. Brown, M. V. Cantarini, C. Morris, I. M. Desar, C. M. van Herpen
Journal: Journal of Clinical Oncology (2008)

3535 Background: AZD6244 is a potent, selective, uncompetitive inhibitor of MEK1/2 being tested in phase II clinical trials for a number of solid tumors. To date, clinical trials have studied a freebase oral suspension formulation. A solid oral formulation, incorporating the hydrogen sulfate salt of AZD6244, has been developed to enable more convenient dosing. Methods: This phase I dose escalation study determines the maximum tolerated dose (MTD), safety and pharmacokinetic (PK) profile of the AZD6244 hydrogen sulfate formulation. Pts with advanced cancer were dosed in sequential cohorts of 6 pts from 25 mg to 100 mg BID. Plasma PK samples were collected at frequent timepoints on days 1 and 8. Results: Twenty-eight pts have been enrolled into this phase of the study. Pts received 25 mg (6), 50 mg (7), 75 mg (7) or 100 mg (8). Frequent tumor types were colorectal (9), melanoma (8), NSCLC (3), and esophageal carcinoma (2). The MTD was 75 mg BID. Three dose-limiting toxicities have been observed: G3 fatigue at 75 mg BID; G3 pleural effusion and G3 rash at 100 mg BID. The most common adverse events were acneiform rash, fatigue, nausea, diarrhea, dyspnea, peripheral edema, and vomiting. Increased blood pressure and asymptomatic LVEF reduction were also observed. Progressive disease was the most common reason for discontinuing treatment. On visual inspection, the AUC is approximately dose proportional across the 25 to 100 mg dose range tested. The median Cmax and AUC for AZD6244 hydrogen sulfate 75 mg BID is higher than historical data for the first-in-human study of the AZD6244 freebase 100 mg BID. Part B is investigating the relative bioavailability of the two formulations. Preliminary data on one pt with melanoma (pretreated with dacarbazine with PD after 6 cycles) reveal a complete response within 16 weeks of commencing therapy. Updated data on all pts will be presented. Conclusions: AZD6244 continues to show promising anti-cancer activity, notably in melanoma. This first-in-human study of the solid oral dosage form of AZD6244 demonstrates that the MTD of this formulation was 75 mg BID. Relative bioavailability studies of this dose, compared with the MTD of the oral suspension formulation, are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca
Development of educational materials about inherited breast cancer in black women
Authors: T. Pal, A. Gjyshi, D. Rivers, E. Rocchio, A. Garcia, G. P. Quinn, S. Vadaparampil
Journal: Journal of Clinical Oncology (2009)

1536 Background: Current educational materials about inherited breast and ovarian cancer (HBOC) have not been culturally tailored for the Black community, which may contribute to lower levels of awareness about this topic. Through an academic and community partnership, realized through a Community Advisory Panel (CAP) comprised of breast cancer survivors, advocates, community leaders, and health care providers, this need was identified. Methods: Utilizing a phased approach implemented through this academic and community partnership, a culturally tailored brochure and booklet about HBOC for the Black community were developed and reviewed. To evaluate the brochure, three focus groups were conducted by race-concordant moderators. HBOC was discussed with Black women from diverse backgrounds, including those with and without breast cancer (n = 46). Summaries were created from audiotapes and handwritten notes and content was analyzed based on Grounded Theory, after which the brochure was revised. Similarly, revisions to the booklet were made based on feedback obtained about the brochure. Materials were then presented to the CAP for re-review. Results: From this iterative process, the key content identified as areas for improvement were: (1) Inclusion of breast cancer information specific to Black women; (2) Use of the term “Black”; (3) Inclusion of African American flag colors; (4) Clarification of the concept of genetic counseling; and (5) Enhancing relevance of information for young women. Conclusions: The CAP and study participants recognized the need for culturally relevant educational materials addressing HBOC in the Black community. Their feedback identified important areas for improvement which have been implemented in the design of a culturally tailored brochure that is available for widespread dissemination. Further evaluation of the booklet is currently in progress. No significant financial relationships to disclose.
Results of 3<sup>rd</sup> line therapy on N9841: a randomized phase III trial of oxaliplatin/5-fluorouracil (5FU)/leucovorin (FOLFOX4) versus irinotecan (CPT-11) in patients (pts) with advanced colorectal cancer (CRC) previously treated with prior 5FU chemotherapy
Authors: K. M. Rowland, H. C. Pitot, D. J. Sargent, P. A. Philip, E. P. Mitchell, J. A. Mailliard, R. M. Goldberg, S. R. Alberts
Journal: Journal of Clinical Oncology (2005)

3519 Background: The primary goal of the Intergroup trial N9841 was to determine whether overall survival (OS) of pts treated with 2nd line FOLFOX4 was equivalent to 2nd line treatment (Rx) with CPT-11 in pts who had failed prior 5FU (either for metastatic disease or ≤ 6 months of adjuvant 5FU Rx). Pts who were crossed over (X-over) to 3rd line Rx after failure on initial protocol Rx are reported here. Methods: Protocol Rx (doses in mg/m2) for FOLFOX4: OXAL 85 d1 + LV 200/5FU 400 bolus + 600 as a 22 hour infusion d1, 2 q2w; and single agent CPT-11: CPT-11 350 d1 q3w (300 for ECOG performance status = 2, age ≥ 70, or prior pelvic radiation). Here we focus only on those pts with X-over, a non-random subset of those enrolled. Results: 491 pts were randomized on the initial protocol between 10/99 to12/03. 220 pts (45%) X-over to protocol mandated 3rd line therapy (CPT-11 to FOLFOX4 - 126, FOLFOX4 to CPT-11 - 94). 3rd line efficacy results (including OS from X-over, time from X-over to progression (TTP), and response rate (RR) to X-over treatment) and common grade 3+ toxicities on protocol Rx are shown in the table below. Responders to 2nd line Rx were twice as likely to respond to 3rd line Rx (18% vs 9%), independent of Rx sequencing; this was of borderline significance (p=0.07). 3rd line Rx with FOLFOX4 was associated with more neutropenia and parasthesias; whereas, CPT-11 was associated with more grade ≥ 3 nausea, vomiting, diarrhea, and febrile neutropenia. Conclusions: Both FOLFOX4 and CPT-11 have activity after failure of both 5-FU and the complementary regimen. Supported by NIH Grant CA25224. Efficacy & Toxicity (≥ Grade 3), by X-Over Regimen Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech, Lilly Oncology, Pfizer, Sanofi Pfizer, Sanofi Pfizer, Sanofi Sanofi
Unrelated Clones In Myelodysplastic Syndromes and Acute Myeloid Leukemia - Characterization and Prognostic Relevance
Authors: Julie Schanz, Fischer Stephanie, Claudia Haferlach, Georgia Bardi, Marilyn L. Slovak, Virginie Eclache, Bertil Johansson, Kazuma Ohyashiki, Francesc Sole, Gabriele Prescher, Michael Pfeilstöcker, Thomas Nösslinger, Christa Fonatsch, Michael Lübbert, Friedrich Wimzal, Reinhard Stauder, Aristoteles Giagounidis, Otto Krieger, Barbara Hildebrandt, Michelle M. Le Beau, John M. Bennett, Peter L. Greenberg, Ulrich Germing, Detlef Haase
Journal: Blood (2010)
Findings from the phase I clinical trials of CX-4945, an orally available inhibitor of CK2.
Authors: R. F. Marschke, M. J. Borad, R. W. McFarland, R. H. Alvarez, J. K. Lim, C. S. Padgett, D. D. Von Hoff, S. E. O'Brien, D. W. Northfelt
Journal: Journal of Clinical Oncology (2011)

3087 Background: CK2 protein kinase is an attractive target for anticancer therapy because it is essential to the survival and maintenance of the cancer phenotype, it is overexpressed in cancer cells, and it supports multiple oncogenic signaling pathways. CX-4945 is a first-in-class, orally available, small molecule with highly selective inhibition of CK2. Methods: Two phase I clinical studies with CX-4945 were conducted in patients with advanced solid tumors in successive escalating dose cohorts. CX-4945 was administered orally on two different dosing schedules; twice daily or four times daily, for the first 3 consecutive weeks of a 4 week cycle. Therapy was continued until the patient showed signs of intolerance to CX-4945, or evidence of disease progression. All patients studied provided blood samples for pharmacokinetic and pharmacodynamic analyses, including the biomarker measurements of IL-6 and IL-8 levels, phosphoproteins to assess the inhibition of CK2 protein kinase in peripheral blood mononuclear cells, and downstream inhibition of the Akt signaling pathway. Results: Forty-three patients received oral doses with CX-4945 in these phase I studies. The maximum tolerated doses (MTDs) were determined for both dosing schedules, and the drug was deemed generally well tolerated. Diarrhea and hypokalemia are the dose limiting toxicities (DLTs), and these toxicities are reversible with drug discontinuation, antidiarrheal use, and potassium supplementation. The pharmacokinetics of CX-4945 were linear and dose dependent, and evidence of biomarker responses in the inhibition of CK2 and Akt pathways were observed in a drug exposure-related manner. No complete or partial RECIST responses were seen, but stable disease for at least 6 months was evident in 15% of treated patients. Conclusions: These studies established that CX-4945 can be orally administered safely on two different dosing schedules. The pharmacokinetics of CX-4945 were dose dependent, and drug exposure related inhibition of the CK2 and Akt pathways were observed. Disease stabilization was evident with CX-4945 as a single agent. Combination phase Ib/II studies in a number of different cancers are planned.
Bevacizumab-related hypertension: Search for underlying mechanisms
Authors: N. Steeghs, T. J. Rabelink, J. op ’t Roodt, E. de Koning, H. Gelderblom
Journal: Journal of Clinical Oncology (2009)

e14520 Background: Hypertension is a commonly observed side effect of inhibitors of VEGF/VEGFR-2 signaling such as bevacizumab. The mechanisms leading to this increase in blood pressure during anti-angiogenic therapy have not been elucidated. Recent studies suggest that functional rarefaction (a decrease in perfused microvessels) or anatomic rarefaction (a reduction in capillary density) may play an important role. The purpose of this study was to search for possible mechanisms that cause hypertension in patients treated with anti-angiogenic therapy and to confirm our hypothesis that systemic inhibition of VEGF inhibits vascular function and causes rarefaction. Methods: Patients treated with bevacizumab for any type of cancer were eligible. Measurements of blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), aortic pulse wave velocity (PWV), and capillary density and diameter with sidestream dark field (SDF) imaging of the mucosal microcirculation of the lip were performed at baseline, after 6 weeks of treatment, and 3 months after discontinuation of bevacizumab treatment. Results: Fourteen patients were included in this study. During bevacizumab treatment the mean systolic and diastolic blood pressure values increased, +3.4 mmHg (p=0.406), and +5.6 mmHg (p=0.023) resp. Mean FMD showed a statistically significant decrease of -3.1% (p=0.006). Mean NMD was unchanged. After 6 weeks treatment mean PWV increased significantly +0.7 m/s (p=0.0.027). A significant reduction in capillary density was seen from 18.0 capillary loops per image at baseline to 12.7 after 6 weeks (p=0.000007). Also a significant reduction in capillary diameter was seen, from 6.9 to 5.6 μm (p=0.002). Results after discontinuation of bevacizumab treatment were not yet available. Conclusions: Rarefaction (reduction in capillary density) and endothelial dysfunction observed in this study provide a plausible mechanism for the increase in blood pressure which results from treatment with bevacizumab. No significant financial relationships to disclose.
A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC)
Authors: G. Hudes, M. Carducci, P. Tomczak, J. Dutcher, R. Figlin, A. Kapoor, E. Staroslawska, T. O’Toole, S. Kong, L. Moore
Journal: Journal of Clinical Oncology (2006)

LBA4 Background: Temsirolimus (TEMSR, CCI-779) is a specific inhibitor of mTOR, a signaling protein that regulates cell growth and angiogenesis. In a single-agent, phase 2 study, TEMSR administration to heavily pretreated patients (pts, n = 111) with adv RCC resulted in a median overall survival (OS) of 15.0 mos (Atkins et al, J Clin Oncol 2004). Retrospectively, 49 pts were categorized in a poor-risk group (Motzer et al, J Clin Oncol 2002). The TEMSR-treated pts in this group had a 1.7-fold longer median OS than the first-line, IFN-treated, poor-risk group reported by Motzer et al. In a phase 1 study, the maximum tolerated dose of the combination of TEMSR + IFN in adv RCC pts was TEMSR 15 mg intravenously (IV) once/wk + IFN 6 million units (MU) subcutaneously (SC) 3 times weekly (TIW) (Smith et al, Proc ASCO 2004). Thus, this phase 3 study in first-line, poor-risk adv RCC pts was initiated in July 2003. Methods: Pts with adv RCC and no prior systemic therapy were enrolled in this open-label study if they had ≥3 of 6 risk factors (the 5 Motzer criteria and &gt;1 metastatic disease site). Pts were randomized (1:1:1) to arm 1, IFN up to 18 MU SC TIW; arm 2, TEMSR 25 mg IV once/wk; or arm 3, TEMSR 15 mg IV once/wk + IFN 6 MU SC TIW. The primary study endpoint was OS; the study was powered to compare the TEMSR arms with the IFN arm. Results: We report 20 Mar 2006 preliminary data from an interim analysis performed by the IDMC. Of the 626 pts enrolled, 442 deaths occurred. Patients treated with TEMSR had a statistically longer survival than those treated with IFN (Table). OS of patients treated with IFN and TEMSR + IFN were not statistically different. The 3 most frequently occurring adverse events ≥gr 3 were asthenia (arm 1: arm 2: arm 3, 27%: 12%: 30% pts), anemia (24%: 21%: 39% pts), and dyspnea (8%: 9%: 11% pts). Conclusions: Single-agent TEMSR significantly increases the OS of first-line, poor-risk adv RCC pts compared with IFN, with an acceptable safety profile. [Table: see text] [Table: see text]
Predictive profiling of 5-fluorouracil (5-FU) resistance in metastatic colorectal cancer (mCRC)
Authors: W. Ichikawa, T. Takahashi, K. Suto, Y. Okayama, E. Toda, T. Oka, S. Okayama, R. Hirayama
Journal: Journal of Clinical Oncology (2005)

3561 Background: The aim of this study is to identify gene expression profile in mCRC that can predict treatment effect by single agent therapy of 5-FU, which was commonly used in the field of clinical practice until 2003 in Japan. Methods: The study population consisted of consecutive 43 patients with mCRC who received the chemotherapy for metastatic disease after resection of primary tumors at Saitama Medical School. All patients were treated with Roswell Park regimen (5-FU 600mg/sqm/day weekly for 6 weeks combined with l-leucovorin (LV) 250mg/sqm/day) under IC. Response rate was 26% with 11 responders and 32 non-responders. Patients were divided into two groups according to median survival time (MST) of 9 months in this cohort; “long” and “short” survivors. RNA extracted from primary tumors were profiled on microarrays consisting of 8,500 genes. Results: Differentially expressed 302 genes according to response were selected by Spearman’s correlation analysis (p<0.05); overexpressed 246 genes and underexpressed 56 genes in responders. The 302 genes included ferredoxin reductase and several key enzymes in pyrimidine metabolism such as dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase, and RNA polymerase. By dimension reduction using partial least squares and classification using logistic discrimination, gene expression profiling identified a 22-gene signature that predicts response to 5-FU/LV, with the greatest estimated accuracy rate of 98% in leave-one-out cross validation analysis. A similar approach identified a 16-gene set that distingushed “long” and “short” survivors, with an accuracy of 100%. This signature was validated in 18 independent pts. The log-rank test indicated a significant difference in survival time between the predicted “long” and “short” survival (MST: 13.0 months versus 5.3 months, p<0.001). Conclusions: These results show the potential of gene expression profiling to predict 5-FU sensitivity, as well as for potential therapeutic targets. No significant financial relationships to disclose.
Differences in CNS metabolism between pups and adults in an animal model of biliary cirrhosis: longitudinal, non-invasive in vivo study
Authors: Cristina Cudalbu, Olivier Braissant, Valerie A. Mclin
Journal: Hepatology (2013)

Keywords: CIBM-AIT Reference EPFL-CONF-189925 Record created on 2013-10-21, modified on 2017-11-27
Demographics from the ETHECC (Evaluation of THYMITAQ [nolatrexed dihydrochloride] in Hepatocellular Carcinoma [HCC]) trial population
Authors: Y. Z. Patt, R. G. Gish, G. Suplick, J. García-Vargas, J. Gallo
Journal: Journal of Clinical Oncology (2005)

4151 Background: ETHECC is a prospective controlled randomized Phase III study in patients w/ unresectable HCC comparing nolatrexed dihydrochloride (THYMITAQ) to doxorubicin (Adriamycin). Nolatrexed is a novel, non-classical anti-folate that passively enters tumor cells in its active form and acts specifically as a Thymidylate Synthase inhibitor. The trial is being conducted in N. America (NA), Europe (EU) and S. Africa (SA) w/ an accrual goal of 446 patients. The objectives of this presentation are to describe risk factors, disease stage and demographic characteristics of a large cohort of patients w/ HCC. Methods: Randomization of patients is stratified by CLIP score and Karnofsky Performance Score (KPS). The results below are based on tables and lists generated for an independent Data Safety Monitoring Board (DSMB) meeting. Data on 294 entrants were available. As required by the DSMB, the data and statistical analysis provided ignored treatment arm and provided information on entire cohort of patients. Results: Geographic distribution: NA, 45.7%; EU, 43.4%; SA, 10.9%. Median age of population: 62.0 years; Median weight and height: 72.7Kg and 170.0cm, respectively. Male-to-female ratio: 4:1. Ethnic distribution: Caucasian, 71.8%; African descent, 15.0%; Asian, 8.2%; Other, 5.1%. Histologic distribution: HCC, 87.4%; Fibrolamellar, 1.4%; Presumptive HCC, 11.3%. Risk factors: HBV, 16.6%; HCV, 27.0%; Alcoholism, 18.6%; Cirrhosis, 37.7%. Extent of disease: Localization to liver, 55.1%; Metastatic, 44.9% (Location: Lymph nodes, 31.1%; Lung, 29.6%; Bone, 14.4%; Other, 25.0%). Severity of Cirrhosis by Child-Pugh classification: A, 72.9%; B, 26.4%; C, 0.7%. HCC stage distribution by CLIP score: 0, 6.8%; 1, 26.4%; 2, 37.0%; 3, 28.8%; 4, 1.0%. KPS distribution: 60, 0.7%; 70, 15.2%; 80, 20.7%; 90, 41.7%; 100, 22.0%. An updated analysis of differences in demographics by region will be discussed at the meeting. Conclusions: ETHECC is the largest clinical trial conducted in the advanced HCC population. Results of this trial will deliver the largest database currently available for demographic characteristics and risk factor information for the Western HCC population (NA, EU). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration EXIMIAS EXIMIAS EXIMIAS EXIMIAS
The relationship and optimal cutoff value between dual phase corrected whole body uptake ratio (CUR) and serum CEA level in recurrent/metastatic colorectal carcinoma: Dual phase whole body protocol using time of flight (TOF) imaging
Authors: S. Oh, S. Kim, K. Jun Suk
Journal: Journal of Clinical Oncology (2009)

e15116 Background: We evaluate whether the corrected SUR has a lineal relationship with a serum CEA level, and to determine the cutoff level of SUV and CEA level in metastatic focus of recurrent colorectal carcinoma. Tumor to background contrast in whole body PET/CT at 1 hour and 2 hour The relationship and optimal cutoff value between change max SUV and serum CEA level in metastatic colorectal carcinoma: ROC analysis. Methods: 48 patients (M: F=32:16, mean age 56.1) who were previously operated for primary colorectal carcinoma enrolled for evaluating metastasis / recurrence from April 2007 to Feb 2008. An one hour and two hour whole body PET/CT (brain to foot) (Gemini TF PET/CT, Philips Medical Systems) was performed after injection of 370–555 MBq of F18 FDG. The serum CEA level (CEA) measured. The time interval between the PET/CT and the CEA 6.8 ± 3.1 days. Background (BG) correct uptake ratio (CUR)[CUR/BG]= maximum SUV of the ROI/ background value (mean SUV of the liver) calculated and then change of the CUR at 1 hour and CUR at 2 hour were calculated. Results: Among the 48 patients, recurrence was confirmed in 41patients, and the remaining 9 patients were disease free. A significant lineal correlation between change of the CUR at 1 hour and CUR at 2 hour and CEA was founded using ROC analysis (P&lt;0.05). The optimal cutoff value of the change of the CUR at 1 hour and CUR at 2 hour and CEA were 71 % (sensitivity86.7, specificity 83.3, AUC 0.8780.047) and 9.44ng/ml (sensitivity 73.3, specificity 87.5, AUC 0.857±0.051) respectively. The difference of AUC between the change of the CUR at 1 hour and CUR at 2 hour and CEA was not significantly different (0.022±0.065, P = 0.739). Conclusions: The change of CUR of 70 % and the CEA level of 9.44 ng/ml was best cutoff value in detecting the recurrent/metastatic focus in colorectal carcinoma. No significant financial relationships to disclose.