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  • 1
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    Phase I Trial of BAY 50-4798, an Interleukin-2–Specific Agonist in Advanced Melanoma and Renal Cancer
    American Association for Cancer Research (AACR) ; 2007
    In:  Clinical Cancer Research Vol. 13, No. 11 ( 2007-06-01), p. 3312-3319
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 11 ( 2007-06-01), p. 3312-3319
    Abstract: Purpose: BAY 50-4798 is an analogue of interleukin-2 that selectively activates T cells over natural killer cells. This phase I study was designed to determine the maximum tolerated dose (MTD) and safety of BAY 50-4798, screen for tumor response, and assess pharmacokinetics. Experimental Design: Forty-five patients with metastatic melanoma or renal cancer were enrolled, 31 on escalating doses to determine the MTD, with 20 renal cell carcinoma patients treated at MTD to detect antitumor activity. BAY 50-4798 was delivered i.v. every 8 h, days 1 to 5 and 15 to 19, and could be repeated after 9 weeks if tumor was stable or responding. Results: The MTD was defined by and reported in terms of doses received. The doses tested ranged from 1.3 to 26.1 μg/kg, and the MTD was defined as 10.4 μg/kg based on toxicities similar to those of aldesleukin. Two patients achieved partial responses, one with melanoma and one with renal cell carcinoma. Among all 45 patients, 53% and 9% experienced a grade 3 and 4 toxicity, respectively. Among the patients treated at the MTD of 10.4 μg/kg, 71% and 10% experienced a grade 3 and 4 toxicity, respectively. Pharmacokinetics showed dose-dependent peak concentrations (Cmax) and area under the curve with a half-life of ∼2 h and no evidence of accumulation. Lymphocyte subset analysis confirmed the preferential expansion of T-cell subsets over natural killer cells. Conclusions: The antitumor activity of BAY 50-4798 in malignancies that respond to high-dose interleukin-2 was low. BAY 50-4798 might provide advantages over aldesleukin in antigen-specific immunotherapies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-1341
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
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    Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors
    American Association for Cancer Research (AACR) ; 2007
    In:  Clinical Cancer Research Vol. 13, No. 16 ( 2007-08-15), p. 4849-4857
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 16 ( 2007-08-15), p. 4849-4857
    Abstract: Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-07-0382
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel
    American Association for Cancer Research (AACR) ; 2008
    In:  Clinical Cancer Research Vol. 14, No. 15 ( 2008-08-01), p. 4836-4842
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 15 ( 2008-08-01), p. 4836-4842
    Abstract: Purpose: This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors. Patients and Methods: Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m2 paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations. Results: Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma. Conclusions: The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m2 paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-07-4123
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
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    Plasma Biomarkers as Predictors of Outcome in Patients with Advanced Hepatocellular Carcinoma
    American Association for Cancer Research (AACR) ; 2012
    In:  Clinical Cancer Research Vol. 18, No. 8 ( 2012-04-15), p. 2290-2300
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 8 ( 2012-04-15), p. 2290-2300
    Abstract: Purpose: Validated biomarkers of prognosis and response to drug have not been identified for patients with hepatocellular carcinoma (HCC). One of the objectives of the phase III, randomized, controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was to explore the ability of plasma biomarkers to predict prognosis and therapeutic efficacy. Experimental Design: In SHARP, 602 patients with advanced HCC were randomized to receive either oral sorafenib 400 mg twice a day per os or matching placebo daily on a continuous basis. Ten plasma biomarkers implicated in the pathogenesis of HCC were measured in 491 patients at baseline and in 305 after 12 weeks of treatment. The candidate biomarkers were analyzed to identify correlates of prognosis or predictors of response to sorafenib. Results: In both the entire patient population and the placebo cohort, baseline angiopoietin 2 (Ang2) and VEGF concentrations independently predicted survival. Clinical variables such as macroscopic vascular invasion, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline α-fetoprotein and alkaline phosphatase concentrations also independently predicted survival in these groups. In the sorafenib cohort, trends toward enhanced survival benefit from sorafenib were observed in patients with high s-c-KIT or low hepatocyte growth factor concentration at baseline (P of interaction = 0.081 and 0.073, respectively). Conclusions: The angiogenesis biomarkers Ang2 and VEGF were independent predictors of survival in patients with advanced HCC. In contrast, none of the biomarkers tested significantly predicted response to sorafenib. Clin Cancer Res; 18(8); 2290–300. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-11-2175
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
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    Safety and Pharmacokinetics of the Dual Action Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor, BAY 43-9006, in Patients with Advanced, Refractory Solid Tumors
    American Association for Cancer Research (AACR) ; 2005
    In:  Clinical Cancer Research Vol. 11, No. 15 ( 2005-08-01), p. 5472-5480
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 15 ( 2005-08-01), p. 5472-5480
    Abstract: Purpose: BAY 43-9006, a novel multikinase inhibitor, prevents tumor growth by combining two antitumor activities: inhibition of both tumor cell proliferation and tumor angiogenesis. This phase I, open-label, nonrandomized, noncontrolled, single-arm, dose escalation study was done to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, effect on biomarkers, and tumor response with BAY 43-9006 in 19 patients with advanced, refractory solid tumors. Experimental Design: BAY 43-9006 was given orally in repeated cycles of 1-week on/1-week off. The study comprised five dose levels, ranging from 100 mg twice daily (bid) to 800 mg bid. Treatment of each patient continued until unacceptable toxicity, tumor progression, or death. Results: Rash and hypertension were the dose-limiting toxicities at the 800 mg bid dose requiring study drug discontinuation; therefore, the MTD of BAY 43-9006 in this study was determined to be 600 mg bid. BAY 43-9006 was generally well tolerated, with mild to moderate toxicities. Pharmacokinetic analysis showed early absorption followed by delayed secondary peaks and slow terminal elimination. Stable disease was achieved in five patients: one patient showed reduced tumor activity (positron emission tomography scan) and reduced mitogen-activated protein kinase signaling (lower phospho-ERK); one patient remained on treatment until study end point. Conclusions: The results confirm the favorable safety profile of BAY 43-9006 and support the development of this compound for the treatment of solid tumors.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-04-2658
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
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    Abstract 304: Comparison of commercially available phospho-AKT [Ser473] antibodies for immunohistochemical biomarker analysis
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 304-304
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 304-304
    Abstract: Immunohistochemical (IHC) analysis of AKT phosphorylation on Ser473 is commonly performed on pre- and post-treatment cancer biopsies as part of pharmacodynamic biomarker assessment for targeted oncology therapeutics. The current study was performed to assess the specificity and sensitivity of four pAKT Ser473 monoclonal antibodies for IHC analysis (clones D9E, 736E11, 587F11 and 14-5). To facilitate this analysis, cancer cell lines with constitutive activation of the PI3K pathway due to mutations in PIK3CA (MCF-7 and MKN-1) or PTEN (MDA-MB-468) were grown in the presence or absence of inhibitors of the PI3K pathway (wortmannin and LY294002). Cell lysates were prepared for analysis via Western blotting and formalin-fixed, paraffin-embedded cell pellets were prepared for analysis via IHC. All antibodies produced a band at 65 kDa, the expected molecular weight for pAKT, when used for Western blot analysis of untreated cell lines and demonstrated a reduction or ablation of this band following treatment of the cell lines with inhibitors of the PI3K pathway. When examined via IHC, antibodies 736E11 and 587F11 demonstrated nuclear and cytoplasmic staining in MCF-7 and MKN-1 cells and membrane staining in MDA-MB-468 cells. These antibodies demonstrated a reduction of staining in all three cell lines treated with PI3K inhibitors, but the reduction was modest in MCF-7 and MKN-1 cells. Clone 587F11 was the least sensitive for IHC. Staining with antibodies 14-5 and D9E was predominantly cytoplasmic or membrane associated, while clone14-5 produced a more punctate appearance. Strong staining was achieved with clone 14-5 and prominent reduction or ablation of staining was observed in all three cell lines treated with PI3K pathway inhibitors. Staining with clone D9E was a little less sensitive than with clone 14-5, but significant reduction or ablation of staining in cell lines treated with PI3K inhibitors was also observed. In summary, clones 14-5 and D9E appear to demonstrate adequate specificity and sensitivity for use in IHC assays. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 304.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-304
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract A43: Detection of tumor-associated KRAS mutations in the plasma and tumor tissue of colorectal cancer patients
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. A43-A43
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. A43-A43
    Abstract: The mutational evaluation of tumor-derived genetic material is becoming increasingly important in the era of personalized medicine. DNA harvested from a variety of sources (e.g., tumor biopsies, plasma, serum, urine and stool) may be useful to determine the mutational status of a tumor. In addition, a variety of methods for performing mutational analyses are available. In the present study, DNA derived from tumor biopsies and plasma was evaluated for KRAS mutational status by two different methodologies: Sequenom and BEAMing. In an initial experiment, KRAS mutations were identified in 36/64 (56%) of colorectal tumors analyzed by the Sequenom method. Matched plasma samples corresponding to a subset of the patients with KRAS-mutant tumors (n = 18) were subsequently evaluated for KRAS mutational status by Sequenom and BEAMing methodologies. Each of these methods detected the expected tumor-associated KRAS mutation in approximately 70% of the plasma samples analyzed. An additional set of 38 plasma samples from late stage metastatic colorectal cancer patients was then evaluated by both Sequenom and BEAMing, which lead to the identification of KRAS mutations in 9/38 (24%) and 19/38 (50%) of the samples analyzed by the respective technologies. Biopsies from 8 of these 38 patients were available and evaluated for KRAS mutational status by Sequenom. In one case, a KRAS mutation was found in the tumor that had not been detected in the corresponding plasma sample, and in another case a KRAS mutation that had been detected in a plasma sample was not detected in the corresponding tumor. This study indicates that the Sequenom method can be successfully used to determine the KRAS mutational status in both tumor biopsies and plasma. The BEAMing method was also successfully used to determine KRAS mutational status in plasma, and appears to be more sensitive than the Sequenom method. Since the frequency of KRAS mutation detected in the plasma of 38 metastatic colorectal cancer patients using BEAMing (i.e., 50%) is similar to that reported in the literature for this patient population when using tumor biopsies for mutational analysis, the assessment of tumor-associated mutations in plasma may represent a viable option in this patient population. However, since the KRAS mutational status in plasma and tumor do not always correspond, data obtained from these two sources should be independently evaluated in the clinical setting. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A43.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-A43
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 8
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    Online Resource
    Validated HPLC/MS/MS assay for CI-1011 in rat plasma and a comparison with an HPLC/UV assay
    Elsevier BV ; 1998
    In:  Journal of Pharmaceutical and Biomedical Analysis Vol. 17, No. 8 ( 1998-9), p. 1399-1413
    Details
    In: Journal of Pharmaceutical and Biomedical Analysis, Elsevier BV, Vol. 17, No. 8 ( 1998-9), p. 1399-1413
    Type of Medium: Online Resource
    ISSN: 0731-7085
    URL: Article
    DOI: 10.1016/S0731-7085(98)00034-X
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1998
    detail.hit.zdb_id: 1491820-1
    SSG: 15,3
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  • 9
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    Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Anti-Cancer Drugs Vol. 20, No. 7 ( 2009-08), p. 616-624
    Details
    In: Anti-Cancer Drugs, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 7 ( 2009-08), p. 616-624
    Type of Medium: Online Resource
    ISSN: 0959-4973
    URL: Article
    DOI: 10.1097/CAD.0b013e32832b2ea0
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
    detail.hit.zdb_id: 2025803-3
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  • 10
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    Distribution of [14C]suramin in tissues of male rats following a single intravenous dose
    Elsevier BV ; 2000
    In:  Life Sciences Vol. 67, No. 15 ( 2000-9), p. 1847-1857
    Details
    In: Life Sciences, Elsevier BV, Vol. 67, No. 15 ( 2000-9), p. 1847-1857
    Type of Medium: Online Resource
    ISSN: 0024-3205
    URL: Article
    DOI: 10.1016/S0024-3205(00)00767-0
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2000
    detail.hit.zdb_id: 2013911-1
    SSG: 12
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