bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study
Authors: Bukowski Ronald , Ernstoff Marc S. , Gore Martin E. , Nemunaitis John J. , Amato Robert , Gupta Samir K. , Tendler Craig L. 
Published: September 2002

PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNα-2b) in patients with advanced solid tumors (primarily RCC). PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 μg/kg/wk of pegylated IFNα-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 μg/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression. RESULTS: The MTD for pegylated IFNα-2b at 12 weeks was 6.0 μg/kg/wk. One year of 6.0 μg/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNα-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months. CONCLUSION: Pegylated IFNα-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 μg/kg/wk.
Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily
Authors: Eder Joseph P. , Supko Jeffrey G. , Clark Jeffrey W. , Puchalski Thomas A. , Garcia-Carbonero Rocio , Ryan David P. , Shulman Lawrence N. , Proper Joann , Kirvan Moira , Rattner Barbara , Connors Susan , Keogan Mary T. , Janicek Milos J. , Fogler William E. , Schnipper Lowell , Kinchla Nancy , Sidor Carolyn , Phillips Eric , Folkman Judah , Kufe Donald W. 
Published: September 2002

PURPOSE: To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors. PATIENTS AND METHODS: The daily dose was increased from 15 to 240 mg/m2 by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin. RESULTS: There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m2/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies. CONCLUSION: rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m2 showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.
Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non–Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial
Authors: Herbst Roy S. , Maddox Anne-Marie , Rothenberg Mace L. , Small Eric J. , Rubin Eric H. , Baselga Jose , Rojo Federico , Hong Waun Ki , Swaisland Helen , Averbuch Steven D. , Ochs Judith , LoRusso Patricia Mucci 
Published: September 2002

PURPOSE: To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS: This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS: Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non–small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses ≥ 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients ≥ 3 months, 22% ≥ 6 months, and 7.2% ≥ 1 year). No relationship between dose, response, or duration on study was observed. CONCLUSION: Rash and diarrhea, generally mild and tolerable at doses ≤ 600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing.
Prognostic Value ofKITMutation Type, Mitotic Activity, and Histologic Subtype in Gastrointestinal Stromal Tumors
Authors: Singer Samuel , Rubin Brian P. , Lux Marcia L. , Chen Chang-Jie , Demetri George D. , Fletcher Christopher D.M. , Fletcher Jonathan A. 
Published: September 2002

PURPOSE: Previous studies have reported clinical correlates for KIT mutations in GISTs, but in most of those studies the KIT mutations were found in less than 50% of the GISTs. The aim of this study was to evaluate the prognostic relevance for KIT mutations in a series of GISTs in which the mutations were evaluated intensively by genomic and cDNA sequencing.PATIENTS AND METHODS: A comprehensive clinical and pathologic analysis of 48 patients with GISTs who had snap-frozen tissue was performed. The median tumor size was 10 cm (range, 2 to 30 cm). Median follow-up for disease-free patients was 48 months. KIT genomic and cDNA was sequenced by using nucleic acid templates isolated from frozen tumors.RESULTS: The overall 5-year recurrence-free survival was 41% ± 6%. Five-year recurrence-free survival for patients with tumors that had mitotic counts of three mitoses or fewer per 30 high-power fields (HPF), more than three to ≤ 15 mitoses per 30 HPF, and more than 15 mitoses per 30 HPF were 89% ± 7%, 49% ± 12%, and 16% ± 6%, respectively (P = .0001). The 32 patients with spindle-cell histology had a 49% ± 7% 5-year recurrence-free survival; in contrast, the 16 patients with epithelioid or mixed histology had a 23% ± 11% 5-year recurrence-free survival (P = .01). Five-year recurrence-free survival for patients with tumors less than 5 cm, 5 to 10 cm, and more than 10 cm were 82% ± 12%, 45% ± 9%, and 27% ± 8%, respectively (P = .03). Prognostic associations were found with particular KIT mutation types, and patients with missense exon 11 mutations had a 5-year recurrence-free survival of 89% ± 11% compared with 40% ± 8% for GISTs with other mutation types (P = .03). The independent predictors for disease-free survival were the presence of deletion/insertion exon 11 mutations (hazard ratio [HR] = 4; P = .006), more than 15 mitoses per 30 HPF (HR = 18; P = .0001), mixed histology (HR = 21; P = .0001), and male sex (HR = 3; P = .05).CONCLUSION: In this series of KIT-expressing GISTs, tumor mitotic activity and histologic subtype were the most important prognostic features. The majority of GISTs contain KIT-activating mutations with the type/location of mutation serving as an independent predictor for disease-free survival. These results suggest that KIT mutation and activation are important in GIST pathogenesis and also may provide important prognostic information.
Study of the Media’s Potential Influence on Prospective Research Participants’ Understanding of and Motivations for Participation in a High-Profile Phase I Trial
Authors: Pentz Rebecca D. , Flamm Anne L. , Sugarman Jeremy , Cohen Marlene Z. , Daniel Ayers G. , Herbst Roy S. , Abbruzzese James L. 
Published: September 2002

PURPOSE: To describe prospective participants’ initial source of information about, understanding of, and motivation to participate in a phase I clinical trial of the antiangiogenesis agent human recombinant endostatin.PATIENTS AND METHODS: We surveyed 100 of 130 persons referred to the endostatin trial between October 1999 and November 2000 and analyzed media coverage of the agent from 1997 to 2000.RESULTS: Forty-seven percent of survey respondents first heard about the trial from media reports. Fifty-one percent of these subsequently contacted their physicians. Thirty-three percent of respondents correctly understood the purpose of the trial. Seventy-nine respondents were interviewed before they met trial investigators to discuss the trial. Of these, those who first heard about endostatin from the media were five times more likely to understand correctly the trial’s purpose than those who first heard from other sources. Seventy-four percent (70 of 95) of respondents cited hope for personal benefit as the main reason for their willingness to enroll. Those who first heard about endostatin from the media were no more motivated by hope of personal benefit (77%) than those who first heard from other sources (71%) (P = .46). Ninety-nine percent of all respondents cited “joining the study gives me hope” as a contributing factor in their decision making about the trial.CONCLUSION: Media coverage prompted prospective participants to contact their physicians but did not seem to hinder understanding nor could it be shown to heighten their hope for personal benefit.
Development of Biologic Markers of Response and Assessment of Antiangiogenic Activity in a Clinical Trial of Human Recombinant Endostatin
Authors: Herbst Roy S. , Mullani Nizar A. , Davis Darren W. , Hess Kenneth R. , McConkey David J. , Charnsangavej Chusilp , O’Reilly Michael S. , Kim Hyung-Woo , Baker Cheryl , Roach Jennifer , Ellis Lee M. , Rashid Asif , Pluda James , Bucana Corazon , Madden Timothy L. , Tran Hai T. , Abbruzzese James L. 
Published: September 2002

PURPOSE: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. PATIENTS AND METHODS: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. RESULTS: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P = .027) and endothelial cell apoptosis (P = .027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. CONCLUSION: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.
Treatment of Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Type With Cladribine: A Phase II Study
Authors: Jäger Gerald , Neumeister Peter , Brezinschek Ruth , Hinterleitner Thomas , Fiebiger Wolfgang , Penz Melitta , Neumann Hans J. , Mlineritsch Brigitte , DeSantis Maria , Quehenberger Franz , Chott Andreas , Beham-Schmid Christine , Höfler Gerald , Linkesch Werner , Raderer Markus 
Published: September 2002

PURPOSE: As chemotherapy has not been extensively studied in patients with lymphoma of the mucosa-associated lymphoid tissue (MALT), we initiated a prospective study to evaluate the activity of the nucleoside analog cladribine (2-chlorodeoxyadenosine [2-CdA]) in this disease. PATIENTS AND METHODS: Patients with histologically verified MALT-type lymphoma were enrolled. 2-CdA was administered at a dose of 0.12 mg/kg body weight on 5 consecutive days, as a 2-hour infusion. Cycles were repeated every 4 weeks for a maximum of six cycles. RESULTS: Nineteen patients with gastric and seven patients with extragastric MALT lymphoma were enrolled. All patients were chemotherapy-naive, and two had been locally irradiated before systemic relapse of the lymphoma. A total of 102 cycles was administered to our patients (median number of cycles per patient, four). All 25 assessable patients responded to treatment: 21 patients (84%) achieved complete remission (CR) and four patients achieved partial remission. All patients (100%) with gastric presentation, but only three patients (43%) with extragastric presentation, achieved CR. Toxicities were moderate and mainly hematologic and required dose reduction and/or premature discontinuation of therapy in only three cases. Two patients died from vascular events, one shortly after the first cycle because of myocardial infarction and the other from stroke 3 months after the second course. Three patients relapsed after 13, 18, and 22 months and one patient showed progressive disease after 15 months. At present, 24 patients are alive at a median follow-up time of 32 months. CONCLUSION: Our data demonstrate that 2-CdA is highly effective in inducing CR in 84% of patients with MALT-type lymphoma.
Alemtuzumab in Previously Treated Chronic Lymphocytic Leukemia Patients Who Also Had Received Fludarabine
Authors: Rai K. R. , Freter C. E. , Mercier R. J. , Cooper M. R. , Mitchell B. S. , Stadtmauer E. A. , Santábarbara P. , Wacker B. , Brettman L. 
Published: September 2002

PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute–sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to ≥ 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to ≥ 42.0 months), and the median survival time was 35.8 months (range, 8.8 to ≥ 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.
Therapy-Related Myeloid Leukemias Are Observed in Patients With Chronic Lymphocytic Leukemia After Treatment With Fludarabine and Chlorambucil: Results of an Intergroup Study, Cancer and Leukemia Group B 9011
Authors: Morrison Vicki A. , Rai Kanti R. , Peterson Bercedis L. , Kolitz Jonathan E. , Elias Laurence , Appelbaum Frederick R. , Hines John D. , Shepherd Lois , Larson Richard A. , Schiffer Charles A. 
Published: September 2002

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin’s lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication. PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML. RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P = .007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months). CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.
Phase II Multicenter Trial of a Weekly Paclitaxel and Carboplatin Regimen in Patients With Advanced Breast Cancer
Authors: Loesch David , Robert Nicholas , Asmar Lina , Gregurich Mary Ann , O’Rourke Mark , Dakhil Shaker , Cox Edwin 
Published: September 2002

PURPOSE: To determine the activity of weekly paclitaxel plus carboplatin as first-line therapy in patients with advanced breast cancer (ABC) by assessing response rate, survival, and safety. PATIENTS AND METHODS: One hundred patients with ABC received paclitaxel 135 mg/m2 (group 1, n = 20) and carboplatin area under the concentration-time curve (AUC) of 2. Paclitaxel was subsequently reduced to 100 mg/m2 (group 2, n = 80) because of toxicity. The median age was 58.5 years, and most patients had an Eastern Cooperative Oncology Group performance status of ≤ 2. Estrogen and progesterone receptor status were evenly distributed among both groups. Sixty-one patients received prior chemotherapy, 37 (61%) of whom received prior doxorubicin. Among 47 patients who received prior hormonal therapy, 43 received tamoxifen. RESULTS: The overall response rate (ORR) among 95 assessable patients was 62%, including 8% complete responses and 54% partial responses. The median time to response was 1.8 months, and the median duration of response was 13.3 months. The median time to progression was 4.8 months. The median survival was 16 months. Neutropenia and leukopenia were the most common grade 3 and 4 toxicities. In group 1, neutropenia (50%) and leukopenia (35%) necessitated dose reductions for 50% of patients during the first three cycles, prompting the reduction in paclitaxel dose to 100 mg/m2. Grade 3 and 4 nonhematologic toxicities for all patients included peripheral neuropathy (11%), infection (6%), anemia (5%), weakness (6%), and paresthesia (3%). CONCLUSION: The 62% ORR achieved with weekly paclitaxel plus carboplatin is among the highest achieved with chemotherapy for ABC. This high response rate and the lack of cardiotoxicity suggest that the regimen should be considered as a nonanthracycline regimen for future adjuvant therapy.
Effects of 5,6-Dimethylxanthenone-4-Acetic Acid on Human Tumor Microcirculation Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging
Authors: Galbraith Susan M. , Rustin Gordon J.S. , Lodge Martin A. , Taylor N. Jane , Stirling J. James , Jameson Michael , Thompson Paul , Hough David , Gumbrell Lindsey , Padhani Anwar R. 
Published: September 2002

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. PATIENTS AND METHODS: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m2 had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity–time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. RESULTS: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. CONCLUSION: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.