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81.
R J Motzer A Rakhit J A Thompson J Nemunaitis B A Murphy J Ellerhorst L H Schwartz W J Berg R M Bukowski 《Journal of interferon & cytokine research》2001,21(4):257-263
Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial. A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2. Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions. The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority. 相似文献
82.
83.
Myeloid-derived suppressor cells: A novel therapeutic target 总被引:1,自引:0,他引:1
Immunotherapy and angiogenic inhibitors, used alone or in combination with chemotherapy, represent two promising cancer treatment
programs. Each is limited by myeloid-derived suppressor cells (MDSCs), which accumulate in tumor-bearing hosts. MDSCs inhibit
effector T-cell function and thus prevent the formation and execution of an effective antitumor immune response. Recently
reported studies have shown that MDSCs also function to promote tumordependent angiogenesis as well as tumor metastasis, and
to provide tumor resistance to antiangiogenic drugs. Insights into tumor-imposed dynamic changes in bone marrow function and
myeloid cell development should fuel novel drug developments and novel applications of drugs currently in use. Such insights
suggest that multitargeted receptor tyrosine kinase inhibitors, such as sunitinib, may be useful adjunctive agents for use
in immunotherapy trials treating several tumor types. 相似文献
84.
George S Kasimis BS Cogswell J Schwarzenberger P Shapiro GI Fidias P Bukowski RM 《Clinical lung cancer》2008,9(3):160-165
PURPOSE: The aim of this study was to evaluate the safety and tolerability of escalating doses of flavopiridol/ paclitaxel/carboplatin in patients with advanced-stage non-small-cell lung cancer (NSCLC) as well as the pharmacokinetics and activity of flavopiridol when used in combination with paclitaxel/carboplatin. PATIENTS AND METHODS: Eligible patients aged 18-75 years with previously untreated stage IIIB/IV NSCLC received paclitaxel 175 mg/m2 over 3 hours followed by carboplatin area under the curve (AUC) 5 over 1 hour and flavopiridol 30-85 mg/m2 over 24 hours every 3 weeks for 3 cycles. RESULTS: Eighteen patients were enrolled at 4 sites in the United States and received flavopiridol 30 mg/m2 (n = 3), 50 mg/m2 (n = 6), 70 mg/m2 (n = 3), or 85 mg/m2 (n = 6). No dose-limiting toxicities (DLTs) occurred at the 50-mg/m2 or 70-mg/m2 dose levels. Two patients treated at the 85-mg/m2 dose level experienced cardiovascular events that did not meet the criteria for DLT but were fatal in 1 case, prompting no further flavopiridol dose escalations and establishment of 70 mg/m2 as the maximum tolerated dose. The most frequently reported adverse events across all dose levels combined were nausea (89%), asthenia (67%), and diarrhea (56%). Flavopiridol concentrations increased rapidly, reached a plateau, and showed a multiphasic decline after the 24-hour infusion. Of 12 patients evaluable for efficacy, 8 achieved a partial response, and 4 had stable disease. CONCLUSION: Flavopiridol in doses 相似文献
85.
Phase 2 trial of talactoferrin in previously treated patients with metastatic renal cell carcinoma 总被引:2,自引:0,他引:2
Jonasch E Stadler WM Bukowski RM Hayes TG Varadhachary A Malik R Figlin RA Srinivas S 《Cancer》2008,113(1):72-77
BACKGROUND: Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC). METHODS: Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival. RESULTS: TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months. CONCLUSIONS: TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational. 相似文献
86.
Motzer RJ Bukowski RM Figlin RA Hutson TE Michaelson MD Kim ST Baum CM Kattan MW 《Cancer》2008,113(7):1552-1558
BACKGROUND.
In a randomized, phase 3 trial, sunitinib demonstrated superior efficacy over interferon‐alfa as first‐line therapy in patients with metastatic clear‐cell renal cell carcinoma (RCC). On the basis of outcome data from that trial, the authors developed a nomogram for predicting the probability of 12‐month progression‐free survival for patients who received sunitinib therapy.METHODS.
Three‐hundred seventy‐five patients who received sunitinib in the phase 3 trial were the subject of the current analysis. Nomogram pretreatment predictor variables included corrected serum calcium levels, the number of metastatic sites, hemoglobin levels, prior nephrectomy, the presence of lung and liver metastases, thrombocytosis, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, and serum levels of alkaline phosphatase and lactate dehydrogenase. Investigator‐assessed progression‐free survival was the predicted outcome endpoint. Internal validation of the nomogram consisted of quantification of the discrimination with the concordance index and assessment of calibration.RESULTS.
One‐hundred seventy‐four of 375 patients (46%) who received sunitinib achieved an objective response, and the median progression‐free survival was 10.8 months (95% confidence interval, 10.6‐12.6 months). A nomogram for predicting the probability of 12‐month progression‐free survival for patients who received sunitinib therapy was constructed on the basis of a Cox regression model from 11 parameters that were determined before treatment. The concordance index was 0.633.CONCLUSIONS.
A nomogram was developed from pretreatment clinical features to predict the probability of achieving 12‐month progression‐free survival with sunitinib therapy for metastatic clear‐cell RCC. The authors concluded that independent validation of the nomogram and additional studies to identify tumor‐specific prognostic factors are warranted. Cancer 2008. © 2008 American Cancer Society. 相似文献87.
George S Hutson TE Mekhail T Wood L Finke J Elson P Dreicer R Bukowski RM 《Cancer chemotherapy and pharmacology》2008,62(2):347-354
PURPOSE: Pegylated interferon alpha-2b (PEG-Intron) is a conjugate of polyethylene glycol (PEG) and interferon alpha-2b, has a prolonged half-life, and an increased area under the curve (AUC) for interferon alpha-2b. The combination of PEG-Intron with recombinant interleukin-2 (rIL-2) was investigated in a phase 1 trial. To determine the maximal tolerable dose (MTD) and preliminary efficacy of concurrent subcutaneous (SC) administration of PEG-Intron and rIL-2 in patients with metastatic renal cell carcinoma (RCC). METHODS: Cohorts of 3-6 patients received escalating doses of PEG-Intron (I-1.5, II- 1.5, III-3.0, IV-3.0, V-4.5 microg/kg SC) given weekly in combination with rIL-2 administered three times weekly (TIW) for 6 weeks. rIL-2 dose levels were escalated in weeks 1 and 4 (I-10.0, II-15.0, III-15.0, IV-20.0, V-20.0 MIU/m(2) SC), and 5.0 MIU/m(2) SC TIW was administered during weeks 2, 3, 5 and 6. RESULTS: Thirty-four patients (24 men; 10 women) were accrued at dose levels I (n = 4), II (n = 4), III (n = 6), IV (n = 14), and V (n = 6) between October 2000 and October 2002. All but one patient had prior nephrectomy (n = 33) and all but one patient (97%) had received no prior systemic therapy. Patients received a median of four cycles of treatment (range 1-9). Dose limiting toxicity occurred at dose level V and included grade 4 neutropenia and hypoxemia. A partial response was found in 5 pts (15%). Median progression-free and overall survival were 9.0 (95% C.I. 5.6-13.1 months) and 31.9 months (95% C.I. 17.2-61.9 months), respectively. CONCLUSION: The combination of PEG-Interferon and SC rIL-2 can be administered with acceptable toxicity. 相似文献
88.
S. L. Allen L. P. Schacter S. M. Lichtman R. Bukowski D. Fusco M. Hensley P. O'Dwyer A. Mittelman B. Rosenbloom S. Huybensz 《Investigational new drugs》1996,14(2):213-217
Summary
Purpose: To determine the response rate of patients withrefractory/relapsed non-Hodgkin's lymphoma to treatment with elsamitrucin and to further characterize the toxic effects of elsamitrucin in this group of patients.
Patients and methods: Eligibility required pathologically verified relapsed or refractory non-Hodgkin's lymphoma with no more than two prior chemotherapy regimens for patients with tumors classified by the International Working Formulation (IWF) as A-C and no more than one prior chemotherapy for those with IWF grades D-G. Patients were entered with either normal or impaired bone marrow function, but normal liver function tests were required unless clearly related to lymphomatous involvement of the liver. Elsamitrucin 25 mg/m2 was administered intravenously over 5–10 minutes weekly.
Results: Thirty-one patients entered the study and were treated for a median of six weeks (range 1–42). All patients were évaluable for toxicity and 30 for response. Mild nausea and/or vomiting and asthenia were the most frequently reported adverse events. Four (13%, 95% CI 4.4–31.6%) partial responses were seen along with two (7%) minor responses while 9 (30%) patients had stable disease.
Conclusion: Elsamitrucin showed modest activity in patients with relapsed or refractory non-Hodgkin's lymphoma. Toxicity was relatively mild, consisted mainly of asthenia, nausea and vomiting and did not include myelosuppression. The activity of elsamitrucin in this group of patients and its lack of myelosuppression suggest utility in this disease especially when combined with other proven agents.Presented in part at the 8th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, The Netherlands, March 1994. 相似文献
89.
Ram Ganapathi Peter Gulick Robin Miller Dale Grabowski Rebecca Turinic Rafael Valeunzuela Andrew Fishleder Ronald Bukowski 《Investigational new drugs》1985,3(3):273-277
Summary Heterogeneity in daunorubicin uptake by leukemic blast cells obtained from the bone marrow of 16 patients with acute leukemia (10 acute nonlymphocytic leukemia and 6 acute lymphocytic leukemia) was determined by laser flow cytometry following drug treatment in vitro for 1 hr. Fluorescence profiles of cellular anthracycline levels in the various samples indicated a marked heterogeneity in daunorubicin uptake and the range of detectable drug fluorescent cells was 34% – 99%. A retrospective analysis of disease outcome in these patients who were treated with a daunorubicin or doxorubicin containing induction regimen indicated the following: (a) 8 of 11 patients who entered complete remission had > 80% of leukemic blast cells accumulating detectable amounts of daunorubicin; and (b) 3 of 4 patients who did not respond to chemotherapy had < 40% of the leukemic blast cells accumulating detectable amounts of daunorubicin. These results suggest that laser flow cytometry may be useful in determining qualitative and quantitative differences in daunorubicin levels in heterogeneous tumor cell populations. 相似文献
90.