9 results on '"Kelly, W Kevin"'
Search Results
2. Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer.
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Martin, Darryl T., Hoimes, Christopher J., Kaimakliotis, Hristos Z., Cheng, Christopher J., Zhang, Ke, Liu, Jingchun, Wheeler, Marcia A., Kelly, W. Kevin, Tew, Greg N., Saltzman, W. Mark, and Weiss, Robert M.
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HISTONE deacetylase inhibitors ,UROTHELIUM ,NANOMEDICINE ,BLADDER cancer treatment ,BLADDER cancer patients ,DRUG delivery systems ,INTRAVESICAL administration ,CANCER chemotherapy - Abstract
Abstract: Nearly 40% of patients with non-invasive bladder cancer will progress to invasive disease despite locally-directed therapy. Overcoming the bladder permeability barrier (BPB) is a challenge for intravesical drug delivery. Using the fluorophore coumarin (C6), we synthesized C6-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were surface modified with a novel cell penetrating polymer, poly(guanidinium oxanorbornene) (PGON). Addition of PGON to the NP surface improved tissue penetration by 10-fold in intravesically-treated mouse bladder and ex vivo human ureter. In addition, NP-C6-PGON significantly enhanced intracellular uptake of NPs compared to NPs without PGON. To examine biological activity, we synthesized NPs that were loaded with the histone deacetylase (HDAC) inhibitor belinostat (NP-Bel-PGON). NP-Bel-PGON exhibited a significantly lower IC50 in cultured bladder cancer cells, and sustained hyperacetylation, when compared to unencapsulated belinostat. Xenograft tumors treated with NP-Bel-PGON showed a 70% reduction in volume, and a 2.5-fold higher intratumoral acetyl-H4, when compared to tumors treated with unloaded NP-PGON. From the Clinical Editor: These authors demonstrate that PLGA nanoparticles with PGON surface functionalization result in greatly enhanced cell penetrating capabilities, and present convincing data from a mouse model of bladder cancer for increased chemotherapy efficacy. [Copyright &y& Elsevier]
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- 2013
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3. Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab Plus Doxorubicin in the Treatment of Metastatic Castration-Resistant Prostate Cancer.
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Slovin, Susan F., Kelly, W. Kevin, Wilton, Andrew, Kattan, Michael, Myskowski, Patricia, Mendelsohn, John, and Scher, Howard I.
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PROSTATE cancer treatment , *DOXORUBICIN , *EPIDERMAL growth factor , *CETUXIMAB , *DRUG dosage , *NEUTROPENIA , *EXANTHEMA , *DRUG therapy , *THERAPEUTIC use of monoclonal antibodies , *THERAPEUTICS - Abstract
Purpose: An open-label, dose-escalating phase Ib/IIa trial was performed to establish a safety profile of ascending doses of cetuximab (IMC C225) in combination with doxorubicin administered weekly for 6 treatments in patients with metastatic castration-resistant prostate cancer. The secondary endpoint was to assess the efficacy of cetuximab in combination with doxorubicin as well as to determine the optimal biologic dose and the maximum tolerated dose. Patients and Methods: Patients in 8 groups received escalating doses of cetuximab 20-300 mg/m2 plus doxorubicin 15 or 20 mg/m2 given intravenously weekly for 6 consecutive weeks, followed by a 1-week observation period. A treatment response was defined as a > 50% decline in prostate-specific antigen (PSA) or regression of radiographically measurable disease. Results: Of the 36 treated patients, 25% had grade 2 neutropenia, 39% had leukopenia, and 44% had stomatitis at doxorubicin 20 mg/m2. Erythematous skin exanthema was seen in 38% of the patients. There was no significant regression of bone or soft tissue disease, but stable disease was observed in 20 (65%) of the 31 patients with bone disease and 14 (61%) of the 23 patients with lymph node disease. Declines in PSA were modest in the 36 patients, with 1 (2.7%) with an 80% decline from baseline, 2 (5.6%) with > 50% to < 80% declines, and 14 (39%) with progression. Median survival was approximately 18 months. Conclusion: In a heavily pretreated population of men with metastatic castration-resistant prostate cancer, this study of cetuximab/doxorubicin was associated with minimal PSA declines posttherapy, though median survival was longer compared to historical control groups. Further studies with cetuximab combined with more contemporary chemotherapy for castration-resistant prostate cancer might be warranted. [ABSTRACT FROM AUTHOR]
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- 2009
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4. Estimating survival benefit in castrate metastatic prostate cancer: decision making in proceeding to a definitive phase III trial
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Verbel, David Andrew, Kelly, W. Kevin, Smaletz, Oren, Regan, Kevin, Curley, Tracy, Heller, Glenn, and Scher, Howard I.
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CANCER patients , *CANCER-related mortality - Abstract
: ObjectivesIn designing a Phase II trial, the acceptable clinical activity region for a new therapy is often developed using data from historically treated patients. This region incorrectly ignores the variability of this estimate, because the efficacy of the prior treatment lies somewhere around the estimate. The size of this interval is dependent on the sample size used. This report illustrates the use of a published method that accounts for this uncertainty and aids in the decision to proceed to a definitive trial.: MethodsA historical data set of low-risk patients with progressive castrate metastatic prostate cancer and a group of similar patients treated in a Phase II chemotherapy trial were used. The 1-year Kaplan-Meier estimate of survival was obtained for both. This approach uses the 75% upper confidence bound of the 1-year survival probability from the historical data set to define the lower limit of acceptable clinical activity. Use of this bound makes the approach more conservative, and hence the decision to proceed to a Phase III trial more difficult.: ResultsIn the low-risk historical patients, the 1-year Kaplan-Meier estimate of survival was 66.4% (75% upper confidence bound 71.0%). In the Phase II patients, the 1-year Kaplan-Meier estimate of survival was 89.5% (95% lower confidence bound 78.2%).: ConclusionsA hypothesis test using the 75% upper confidence bound to define the lower limit of acceptable clinical activity demonstrates that the 1-year survival probability on Taxol/estramustine/carboplatin is greater than that of the historical population, and hence should be taken into a definitive trial. The design provides investigators increased confidence in making this decision. [Copyright &y& Elsevier]
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- 2003
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5. Effect of docetaxel on safety and efficacy of radium-223.
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Den, Robert B and Kelly, W Kevin
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DOCETAXEL , *MEDICATION safety , *DRUG efficacy , *RADIUMTHERAPY , *PROSTATE cancer , *CANCER chemotherapy - Published
- 2014
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6. Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study.
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Lin, Daniel W., Shih, Mei-Chiung, Aronson, William, Basler, Joseph, Beer, Tomasz M., Brophy, Mary, Cooperberg, Matthew, Garzotto, Mark, Kelly, W. Kevin, Lee, Kelvin, McGuire, Valerie, Wang, Yajie, Lu, Ying, Markle, Vivian, Nseyo, Unyime, Ringer, Robert, Savage, Stephen J., Sinnott, Patricia, Uchio, Edward, and Yang, Claire C.
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FEBRILE neutropenia , *CASTRATION-resistant prostate cancer , *TUMOR classification , *PROSTATECTOMY , *CANCER chemotherapy , *GLEASON grading system , *RETROPUBIC prostatectomy , *ADJUVANT treatment of cancer , *PROSTATE-specific antigen - Abstract
The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer–specific, and metastasis-free survival, and time to androgen deprivation therapy. A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2–103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p = 0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58–1.11; p = 0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32–0.92; p = 0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43–0.99; p = 0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage ≥ pT3b (ClinicalTrials.gov number NCT00132301). In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit. In men undergoing radical prostatectomy for clinically localized high-risk prostate cancer, adjuvant docetaxel chemotherapy did not lead to statistically significant improvement in progression-free survival, although prespecified subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage ≥pT3b pathology. [ABSTRACT FROM AUTHOR]
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- 2020
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7. Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation and Androgen Deprivation Therapy for the Treatment of High-Risk Prostate Cancer.
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Lin, Jianqing, Den, Robert B., Greenspan, Jacob, Showalter, Timothy N., Hoffman-Censits, Jean H., Lallas, Costas D., Trabulsi, Edouard J., Gomella, Leonard G., Hurwitz, Mark D., Leiby, Benjamin, Dicker, Adam P., and Kelly, W. Kevin
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PROSTATE cancer , *CABAZITAXEL , *ANDROGENS , *QUALITY of life , *PROGRESSION-free survival , *MEDICAL quality control , *SAFETY , *ANTIANDROGENS , *CLINICAL trials , *METASTASIS , *HYDROCARBONS , *DOSE-response relationship (Radiation) , *DRUG administration , *TREATMENT effectiveness , *DOSE-effect relationship in pharmacology , *RESEARCH funding , *RADIOTHERAPY , *COMBINED modality therapy , *PROSTATE tumors - Abstract
Purpose: Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer.Methods and Materials: Twenty men were enrolled in this institutuional review board-approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition.Results: With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m2. The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain.Conclusions: This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m2. Despite the aggressive nature of the disease, robust biochemical control was observed. [ABSTRACT FROM AUTHOR]- Published
- 2020
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8. Genomic Prostate Cancer Classifier Predicts Biochemical Failure and Metastases in Patients After Postoperative Radiation Therapy.
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Den, Robert B., Feng, Felix Y., Showalter, Timothy N., Mishra, Mark V., Trabulsi, Edouard J., Lallas, Costas D., Gomella, Leonard G., Kelly, W. Kevin, Birbe, Ruth C., McCue, Peter A., Ghadessi, Mercedeh, Yousefi, Kasra, Davicioni, Elai, Knudsen, Karen E., and Dicker, Adam P.
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POSTOPERATIVE care , *RADIOTHERAPY , *PROSTATE cancer patients , *RNA , *OLIGONUCLEOTIDE arrays , *HEALTH outcome assessment - Abstract
Purpose To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP). Methods and Materials Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms. Results The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups. Conclusion The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision-making for treatment of high-risk prostate cancer. [ABSTRACT FROM AUTHOR]
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- 2014
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9. Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data
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Fizazi, Karim, Le Maitre, Aurelie, Hudes, Gary, Berry, William R, Kelly, W Kevin, Eymard, Jean-Christophe, Logothetis, Christopher J, Pignon, Jean-Pierre, and Michiels, Stefan
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DRUG therapy , *PROSTATE cancer , *CANCER chemotherapy , *CANCER treatment , *ANTINEOPLASTIC agents - Abstract
Summary: Background: Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer. Methods: We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used. Findings: The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2·8 years (range 0·0–3·4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0·0001), use of chemotherapy plus estramustine (p=0·008), performance status (p=0·002), and serum PSA concentrations (p=0·04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0·77 [95% CI 0·63–0·93], p=0·008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9·5% (SE 4·0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0·53 [0·38–0·72], p<0·0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0·74 [0·58–0·94], p=0·01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275). Interpretation: In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine. [Copyright &y& Elsevier]
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- 2007
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