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  • American Society of Clinical Oncology (ASCO)  (6)
  • 2010-2014  (6)
  • 1
    Online Resource
    Online Resource
    A phase II study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer (CRPC): A PCCTC trial.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 4654-4654
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 4654-4654
    Abstract: 4654 Background: KX2-391 is an oral small molecule inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, PSA declines were seen in men with advanced prostate cancer. Methods: A single-arm phase 2 study of KX2-391 in 31 men with chemo-naïve bone-metastatic CRPC was conducted at 5 PCCTC sites. Men received oral KX2-391 (40 mg BID) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) at 24 wk (progression = clinical/radiographic progression or death, but not rising PSA; PCWG2 criteria); a 50% success rate was predefined as clinically significant. Secondary endpoints were PSA progression-free survival (PPFS) at 24 wk (PSA progression = 25% PSA rise above nadir; PCWG2 criteria); median PFS; median PPFS; and max PSA decline. Exploratory outcomes included PK studies, CTC enumeration, and analysis of markers of bone resorption (urinary N-telopeptide [uNTx]; C-telopeptide [CTx] ) and formation (bone alk phos [BAP]; osteocalcin). Results: The trial closed early after accrual of 31 men, due to a prespecified futility rule. In all, 26/31 men were evaluable for the primary endpoint; efficacy results are shown below. Also, 2/11 men (18%) with unfavorable (≥5) CTCs at baseline converted to favorable ( 〈 5) CTC counts on study, and 18/19 men (95%) with baseline favorable CTC counts maintained them. The proportion of men with declines in bone turnover markers was 32% (8/25) for uNTx, 21% (6/29) for CTx, 10% (3/29) for BAP, and 25% (7/28) for osteocalcin. In PK studies, median C max was 61 (range 16–129) ng/mL, and AUC was 156 (35–348) ng*hr/mL. Common toxicities (≥10%) included LFT elevations, leukopenia, thrombocytopenia, fatigue, nausea and constipation. Conclusions: KX2-391 dosed at 40 mg BID lacks antitumor activity in men with CRPC, but modulates bone turnover markers in some men. Because a C max of 〉 142 ng/mL is required for tubulin polymerization inhibition, higher once-daily dosing will be used in future trials. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.4654
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Persistent Overall Survival Benefit and No Increased Risk of Second Malignancies With Bortezomib-Melphalan-Prednisone Versus Melphalan-Prednisone in Patients With Previously Untreated Multiple Myeloma
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 4 ( 2013-02-01), p. 448-455
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 4 ( 2013-02-01), p. 448-455
    Abstract: This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies. Patients and Methods In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients. Results After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P 〈 .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance 〈 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P 〈 .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates. Conclusion VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2012.41.6180
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
    Online Resource
    Application of mechanism-based PKPD model to identify optimal dosing regimens for future development of oraxol.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. e13505-e13505
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e13505-e13505
    Abstract: e13505 Background: Paclitaxel (PTX) is a widely used potent anticancer drug that blocks mitosis by stabilization of microtubules. Previous attempts for oral administration of PTX have been unsuccessful at least partly due to its affinity for the efflux pump, P-gp. Oraxol is an oral formulation of PTX combined with a novel potent P-gp inhibitor, HM30181A, to maximize absorption of paclitaxel without itself being systemically absorbed. A population PK/PD model was developed to characterize the temporal relationship between PTX exposure and neutropenia, and subsequently model-based simulations were utilized to determine the optimal dosing strategy for oraxol. Methods: Oraxol was administered to 68 (51M/17F) patients with various malignancies. Oraxol dose levels ranged from 60 to 420 mg/m 2 QW, and 90-150 QWx2 for 3/4 weeks. Population PKPD modeling was performed with the following patient factors: [BSA (1.29-2.15 m 2 ), ECOG PS scores (97% pts ≤ 1), age (36-81.4 yrs), CrCL (39.6-132.8 ml/min), ALB (2.3-4.8 mg/dL), ALT (6-61 IU/L), TBIL (0.2-1.6 mg/dL), and smoking status (NS:57%)]; followed by model validation. Simulations assessed the influence of dose and schedule on the time course and the extent of neutropenia. Results: A precursor-dependent indirect PKPD response model, including three transit compartments was employed to describe the time course of ANC after oraxol administration. Mean predicted (%SEM) baseline ANC and MTT of neutrophils in plasma were 3.6 (3.9) x10 9 cells/L and 6.3 (4.2) days. The magnitude of the inhibition on marrow cells was 3.3% per 100 ng/mL of PTX. Model validation results showed excellent concordance with the observed and simulated ANC profiles at the 150 mg/m 2 dose level. Simulations showed that severity of neutropenia was dose- and schedule-dependent. The optimal dosing scenarios for oraxol 150 mg/m 2 QDx3 and QDx5 showed the incidence of grade ³3 neutropenia to be 53.8% and 58%, respectively. Simulated grade 4 neutropenia was 25 and 34.6% for the same regimens; similar to IV PTX. Conclusions: A PKPD model quantifying the neutropenic effect of oraxol has been developed. The model predicts that the QDx3 or QDx5 oraxol dosing 3/4 weeks may optimize efficacy with manageable toxicity.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.e13505
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Macrophage inhibitory cytokine 1 plasma levels in testicular cancer patients during cisplatin combination treatment and their relation to endothelial damage.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. e15035-e15035
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e15035-e15035
    Abstract: e15035 Background: Chemotherapy- (CTx) related endothelial damage contributes to cardiovascular morbidity in testicular cancer (TC) patients (pts). We used an unbiased translational approach to identify mechanisms of and potential biomarkers for this damage. Methods: During varying time periods human microvascular endothelial cells (HMEC-1) were in vitro exposed to bleomycin, cisplatin or left untreated. From 18k cDNA microarray expression signals were obtained, and quantified with an Affymetrix GMS428 scanner. Differences were analysed at single gene and pathway level, and validated by qRT-PCR. With ELISA, protein levels of 1 candidate biomarker were measured in TC pt plasma before, during and 1 month after bleomycin etoposide cisplatin CTx. Levels were related to endothelial damage plasma markers (von Willebrand Factor [vWF], high-sensitivity C-Reactive Protein [hs-CRP] ). Results: Microarray data from 16k genes identified several genes with highly differential expression; Macrophage Inhibitory Cytokine 1(MIC-1), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG) had strong differences in 〉 1 experimental setting. We regarded these plausible candidates, and confirmed changes by qRT-PCR. Pathway analysis showed a strong association with ‘P53’ and ‘Diabetes Mellitus’ gene sets. Based on known function, we chose to validate MIC-1 protein levels in 41 TC pts. Pre-CTx MIC-1 levels did not differ from healthy controls (TC pts median 383 pg/mL [range 187-1935] vs 340 pg/mL [range 213-504] , p=0.06). During CTx levels of MIC-1, vWF and hsCRP significantly increased. MIC-1 levels correlated with vWF and hsCRP at baseline (vWF r s = 0.35, P=0.03; hsCRP r s = 0.39, P=0.01), during (hsCRP at cycle 1d 8 r s = 0.44, P=0.01; vWF at cycle 3 d8 r s = 0.40, P=0.02) and after CTx (vWF r s = 0.56; P 〈 0.01). Conclusions: An unbiased approach in a preclinical model revealed a set of genes related to bleomycin- and cisplatin-induced endothelial activation, such as MIC-1. The increases in plasma levels and the association with vWF and hsCRP suggest that MIC-1 may be a biomarker for CTx-related endothelial damage. Supported by Dutch Cancer Society grant 2009-4365.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.e15035
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Prospective International Multicenter Phase II Trial of Intravenous Pegylated Liposomal Doxorubicin Monochemotherapy in Patients With Stage IIB, IVA, or IVB Advanced Mycosis Fungoides: Final Results From EORTC 21012
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 33 ( 2012-11-20), p. 4091-4097
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 33 ( 2012-11-20), p. 4091-4097
    Abstract: Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF. Patients and Methods Eligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m 2 on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR). Results Nine centers recruited 49 eligible patients. The median number of chemotherapy cycles received was five. There were no grade 3 to 4 hematologic toxicities. Grade 3 or 4 nonhematologic/nonbiochemical toxicities included cardiac symptom (2%), allergy/hypersensitivity (2%), constitutional symptom (4%), hand and foot reaction (2%), other dermatologic toxicity (6%), other GI toxicity (4%), infection (4%), pulmonary embolism (2%), and cardiac ischemia (2%). Of 49 patients, 20 (40.8%) were responders (complete clinical response [CCR] or partial response [PR] as overall response): three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively. Conclusion PLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2011.39.8065
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 6
    Online Resource
    Online Resource
    Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial
    American Society of Clinical Oncology (ASCO) ; 2010
    In:  Journal of Clinical Oncology Vol. 28, No. 13 ( 2010-05-01), p. 2259-2266
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 13 ( 2010-05-01), p. 2259-2266
    Abstract: The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. Patients and Methods Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). Results With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P 〈 .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. Conclusion VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent–based treatment until relapse.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2009.26.0638
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2010
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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