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J Baselga

Publications and source records attributed to J Baselga.

At least 19 recordsLinked to original sources
PubMed2007

Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival. PATIENTS AND METHODS: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response. RESULTS: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival. CONCLUSION: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.

Adult↗
PubMed2006

Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors.

BACKGROUND: Gimatecan is an orally bioavailable camptothecin analogue with preclinical findings of promising antitumor activity. A phase I design of concerted dose escalation and dosing duration was implemented to assess the potential schedule dependency of tolerability that emerged from animal studies. PATIENTS AND METHODS: Gimatecan was given daily for five consecutive days per week for 1, 2 or 3 weeks every 28 days. Plasma levels of total gimatecan were measured on the first and the last day of treatment in each schedule. RESULTS: Overall, 108 patients were treated with 0.8-7.2 mg/m(2) of gimatecan per cycle. The main toxicity was myelosuppression with dose-limiting thrombocytopenia. In the 1-, 2- and 3-week schedule, the maximum tolerated doses were 4.5, 5.6 and 6.4 mg/m(2). Diarrhea and asthenia were of low grade and of minor clinical relevance, while the higher incidence of nausea and vomiting in the 1-week schedule required the use of antiemetic prophylaxis. Due to the prolonged half-life (approximately 77 h), the plasma concentration of gimatecan increased from the first to the last day of dosing. Six partial responses were observed. CONCLUSIONS: Tolerability of gimatecan was schedule dependent. Further testing with schedules taking into account its long persistence in human plasma is worthwhile.

Administration, Oral↗
PubMed2005

Novel targeted therapies in the treatment of gastric and esophageal cancer.

Esophageal cancer (EC) and gastric cancer (GC) constitute a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant/neoadjuvant radiotherapy and chemotherapy approaches have increased the survival of patients with loco-regional disease. However, most of the patients with GC or EC have advanced disease either at diagnosis or at follow-up. Despite recent advances in the treatment of advanced disease, these patients still do poorly. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of EC and GC. These therapeutic strategies include EGFR inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinases inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of EC and GC that will probably translate into efficacy advantage in the treatment of these common malignancies.

Antineoplastic Agents↗
PubMed2005

Phase II trial of the novel taxane BMS-184476 as second-line in non-small-cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate the tolerability and efficacy of BMS-184476, an analog of paclitaxel, in patients with advanced non-small-cell lung cancer (NSCLC) progressing or relapsing following at least one prior chemotherapy regimen. PATIENTS AND METHODS: Fifty-six previously treated advanced NSCLC patients received BMS-184476 at a dose of 60 mg/m(2) administered intravenously over 1 h every 21 days. RESULTS: The median number of cycles delivered per patient was five (range one to 17). Dose reduction was required in only 3.8% of cycles. Grade 4 neutropenia occurred in 19.6% of patients, but no grade 4 thrombocytopenia or anemia was reported. Febrile neutropenia was observed in only two (3.6%) patients and there were no life-threatening events. Grade 3/4 peripheral sensory-motor neuropathy was reported in 9% of patients. Other non-hematological toxicities, such as nausea and vomiting, myalgia and arthralgia, diarrhea, and mucositis, were uncommon. Partial responses were observed in eight (14.3%) patients and stable disease in 33 (58.9%). Median progression-free survival was 3.7 months [95% confidence interval (CI) 2.7-5.4] and median overall survival was 10 months (95% CI 6-13.4). CONCLUSIONS: BMS-184476 was well tolerated at the dose of 60 mg/m(2) and showed evidence of antitumor activity in previously treated NSCLC.

Adult↗
PubMed2004

Feasibility of CT scan-guided Tru-Cut serial liver biopsies to evaluate pharmacodynamic endpoints in patients with liver metastasis treated with experimental drugs.

We assessed the feasibility of using computed tomographically guided, Tru-Cut serial liver biopsies to perform pharmacodynamic studies in patients with liver metastasis who had been treated with experimental drugs. Twenty-three patients with liver metastasis were enrolled in two protocols for evaluation of the response to two new biologic drugs: a farnesyltransferase inhibitor and a tyrosine kinase inhibitor of the epidermal growth factor receptor. Computed tomographically guided Tru-Cut biopsies with an 18-gauge needle were performed. The procedure was performed at baseline and 2, 6, and 24 h after starting the administration of the drug. The procedures were scheduled on an outpatient basis. We obtained 271 samples (168 from metastatic lesions and 103 from surrounding normal liver tissue) from 23 patients. Biochemical determination of farnesyltransferase activity and different immunohistochemistry stainings (pEGRF, pMAPK, p27, Ki67, and apoptosis) of the signal transduction pathway were determined in each tissue sample, and all scheduled tissue assays were performed with the tissues obtained. Complete serial biopsies were performed in 20 patients. Three patients were excluded due to minor complications after the first biopsy. The morbidity rate in relation to the number of procedures was 1.1% (three of 271 samples). We found serial liver biopsies using Tru-Cut to be a safe and easy procedure. In our series, we could evaluate samples for molecular changes that influence the optimal dose, sequence, and schedule of the new antineoplastic agents.

Alkyl and Aryl Transferases↗
PubMed2004

Fluorescent labels to study thermal transitions in epoxy/silica composites.

The analysis of the fluorescent response from the dansyl moiety as a function of temperature has been used to estimate the thermal transitions in silica particle/epoxy-based composite materials. Silica particles were surface-coated with 3-aminopropyltriethoxysilane (APTES) and 3-aminopropylmethyldiethoxysilane (APDES). 5-Dimethylamino-1-naphtalenesulfonyl chloride (DNS) and 5-dimethylaminonaphthalene-1-(2-aminoehyl)) sulfonamide (DNS-EDA) were selectively attached to the silanized silica particles and to the epoxy matrix respectively. The fluorescence results, interpreted in terms of the model of interpenetrating polymer networks, suggest that (i) independent of the silane coating, the interfacial region is slightly more rigid and heterogeneous than the epoxy bulk and (ii) the interface generated with APTES seems to be more flexible than that obtained with APDES.

Epoxy Compounds↗
PubMed2004

A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer.

BACKGROUND: A phase II randomised trial was conducted to evaluate the tolerability and activity of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. PATIENTS AND METHODS: Eighty-three patients with histologically proven metastatic breast cancer were randomised to receive either docetaxel 40 mg/m2 weekly for 6 consecutive weeks followed by 2 weeks without treatment (n = 41), or docetaxel 100 mg/m2 on day 1 every 3 weeks (n = 42). RESULTS: The incidence of all grade 3-4 adverse events was higher in the 3-weekly group than in the weekly group (96 versus 44), and the number of patients with grade 3-4 adverse events was also greater in the 3-weekly group (31 versus 20). Analysis of individual adverse events tended to favour the weekly regimen. Intent-to-treat overall response rate was 34% and 33% in the weekly and 3-weekly groups, respectively. Median time to progression was 5.7 and 5.3 months after weekly and 3-weekly docetaxel, respectively, and median time to treatment failure was 4.1 and 4.9 months, respectively. CONCLUSION: Weekly docetaxel is an active regimen in metastatic breast cancer with comparable efficacy to 3 weekly docetaxel. Although both schedules were well tolerated, weekly docetaxel appears to have a more favourable toxicity profile.

Adult↗
PubMed2003

Kinetic study of epoxy curing in the glass fiber/epoxy interface using dansyl fluorescence.

The fluorescence response of the dansyl chromophore has been used to study the kinetic of epoxy curing processes. With this new method, comparison between the curing at the interface of a glass fiber/epoxy and in the epoxy bulk of a composite material was studied. The effect of two glass fiber surface treatments was investigated. Commercial E-glass fibers were surface coated with 3-aminopropyltriethoxysilane (APTES) and 3-aminopropylmethyldiethoxysilane (APDES). Fluorimetry (using fluorescent labels) and FT-NIR (Fourier transformed infrared spectroscopy in the near range) techniques were used to monitor the curing process in these composite materials. From the analysis of the data obtained, different simple kinetic models were discussed and apparent activation energies were obtained. Furthermore, from those techniques the respective results were compared to obtain complementary information. Independently of the sample and the technique used for the kinetic analysis, no variation of the activation energy of the epoxy curing reaction was found, which suggests that there are no changes in the mechanism of the reaction along the process. Fluorescence from dansyl located at the glass fiber/epoxy interface reflected that the kind of reinforcement treatment clearly affects the epoxy curing process exactly in that region. However, when analytical response comes from the whole system the mechanism of the reaction does not seem to change with the silane coating used although is quite different in comparison with the process at the interface.

Journal Article↗
PubMed2003

New drugs and new approaches in metastatic bladder cancer.

The median survival of patients with metastatic cancer of the urothelium who receive best supportive care only in 4-6 months. With the introduction of combination chemotherapy regimens including cisplatin and methotrexate for the management of metastatic urothelial cancer, median overall survival has doubled. Nevertheless, death due to cancer ultimately occurs in more than 80% of these patients, thus more effective therapy is required. The new available treatment modalities range from new combinations of conventional chemotherapeutic agents to combinations incorporating novel drugs like gemcitabine and the taxanes. These new combinations incorporate the new active agents in two, three or multiple drug combinations, administered either in one regimen or sequentially in various combinations and schedules intended to improve the outcome of bladder cancer patients. Ongoing phase III studies will help to define the role of these new combinations in the treatment of advanced bladder cancer. The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new prognostic indices that can direct the most appropriate choice of treatment for advanced disease. In addition, advances in the molecular biology of urothelial malignancies may allow identification of specific genetic lesions and biochemical pathways upon which future therapeutic approaches can be focused. The integration of newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression.

Antineoplastic Agents↗
PubMed2003

A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy.

BACKGROUND: We evaluated the efficacy of a single fixed 6 mg dose of pegfilgrastim (a pegylated version of filgrastim) per cycle of chemotherapy, compared with daily administration of filgrastim, in the provision of neutrophil support. PATIENTS AND METHODS: Patients (n = 157) were randomized to receive either a single 6 mg subcutaneous (s.c.) injection of pegfilgrastim or daily 5 mg/kg s.c. injections of filgrastim, after doxorubicin and docetaxel chemotherapy (60 mg/m(2) and 75 mg/m(2), respectively). Duration of grade 4 neutropenia, depth of neutrophil nadir, incidence of febrile neutropenia, time to neutrophil recovery and safety information were recorded. RESULTS: A single 6 mg injection of pegfilgrastim was as effective as daily injections of filgrastim for all efficacy measures for all cycles. The mean duration of grade 4 neutropenia in cycle 1 was 1.8 and 1.6 days for the pegfilgrastim and filgrastim groups, respectively. Results for all efficacy end points in cycles 2-4 were consistent with the results from cycle 1. A trend towards a lower incidence of febrile neutropenia was noted across all cycles with pegfilgrastim compared with filgrastim (13% versus 20%, respectively). A single fixed dose of pegfilgrastim was as safe and well tolerated as standard daily filgrastim. CONCLUSIONS: A single fixed dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelosuppressive chemotherapy. Pegfilgrastim may have utility in other clinical settings of neutropenia.

Adult↗
PubMed2003

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients.

BACKGROUND: This randomized, double-blind, phase II study assessed two doses of the selective estrogen receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed. PATIENTS AND METHODS: Ninety-two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day. Tumor response was assessed using World Health Organization criteria. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) system. Pharmacokinetic data were analyzed using the NONMEM software program (GloboMax, Hanover, MD, USA). RESULTS: Response rates in the 20 mg arm were numerically higher than the 50-mg arm according to the investigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the 20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus 47.7%). Arzoxifene was well tolerated. There were no study drug-related deaths. Mean observed steady-state plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively. CONCLUSIONS: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene. Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.

Aged↗
PubMed2003

Sequential dose-dense paclitaxel followed by topotecan in untreated extensive-stage small-cell lung cancer: a Spanish Lung Cancer Group phase II study.

BACKGROUND: Poor survival rates in extensive-stage small-cell lung cancer (SCLC) patients prompted us to evaluate a sequential dose-dense schedule of paclitaxel followed by topotecan. PATIENTS AND METHODS: Forty-three patients with previously untreated, extensive-stage SCLC received three cycles of paclitaxel 250 mg/m(2) over 3 h every 14 days followed by three cycles of topotecan 2.5 mg/m(2) for 5 days every 21 days. Granulocyte colony-stimulating factor was given after every cycle. Patients progressing at any time and those not achieving complete response (CR) subsequently received four cycles of standard-dose etoposide-cisplatin. RESULTS: A total of 118 cycles of paclitaxel were administered with minimal hematological toxicity. Grade 2/3 peripheral neuropathy was observed in 21% of patients. Response rate to paclitaxel was 48.8%, and 25.6% had stable disease (SD). Thirty-two patients achieving SD or response to paclitaxel subsequently received a total of 90 topotecan cycles. Topotecan-related toxicities included febrile neutropenia in 15.6% of patients with one toxic death, grade 3/4 anemia in 25% of patients and grade 3/4 thrombocytopenia in 31.3%. Non-hematological toxicities were mild. At completion of sequential paclitaxel-topotecan treatment the overall response rate was 55.8% (22 partial response, two CRs). Median survival for all patients was 10.5 months and median progression-free survival was 8.5 months. CONCLUSIONS: Sequential treatment with dose-dense paclitaxel followed by topotecan is feasible despite significant hematological toxicity during topotecan treatment. This schedule is an active regimen in extensive-stage SCLC and merits further investigation.

Adult↗
PubMed2002

Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types.

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

Administration, Oral↗
PubMed2002

Effect of glass fiber surface treatments on mechanical strength of epoxy based composite materials.

Sizing glass fibers with silane coupling agents enhances the adhesion and the durability of the fiber/polymer matrix interface in composite materials. There are several tests to determine the interfacial strength between a fiber and resin, but all of them present difficulties in interpreting the results and/or sample preparation. In this study, we observed the influence of different aminosilanes fiber coatings on the resistance of epoxy-based composite materials using a very easy fractographic test. In addition, we tried a new fluorescence method to get information on a molecular level precisely at the interface. Strength was taken into account from two standpoints: (i) mechanical strength and (ii) the resistance to hydrolysis of the interface in oriented glass-reinforced epoxy-based composites. Three silanes: gamma-aminopropyltriethoxysilane, gamma-Aminopropylmethyldiethoxysilane, and gamma-Aminopropyldimethylethoxysilane were used to obtain different molecular structures at the interface. It was concluded that: (i) the more accessible amine groups are, the higher the interface rigidity is; (ii) an interpenetrating network mechanism seems to be the most important for adhesion and therefore to the interfacial strength; and (iii) the higher the degree of crosslinking in the silane coupling layer is, the higher the hydrolytic damage rate is.

Journal Article↗
PubMed2002

Feasibility trial of methotrexate-paclitaxel as a second line therapy in advanced urothelial cancer.

To evaluate the clinical value of the concurrent use of methotrexate administered immediately before paclitaxel, we investigated the efficacy and toxicity of this two-drug combination administered as palliative second line therapy in patients with advanced urothelial cancer. The design of the schedule and sequence used was based on our previous preclinical data from a comparative study on sequential combinations of paclitaxel and methotrexate in a human bladder cancer cell line. As a confirmation study, we further extended our analysis of in vitro synergism. Twenty patients with advanced transitional cell carcinoma of the urinary tract previously treated with platinum-based therapy, with adequate renal function and a performance status > or = 60 were considered eligible. They received therapy with methotrexate 30 mg/m2 administered as an intravenous bolus, followed immediately by paclitaxel 175 mg/m2 given as a 3-hr infusion, both on day 1 every 21 days. Therapy was given on a compassionate-use basis until either disease progression was documented or the patient became intolerant to therapy. In vitro data were further analyzed using the median-effect principle and the combination index method. Twenty patients with metastatic (16 patients) or locally advanced disease (four patients) received a median of three cycles of therapy. Of the 19 patients assessable for response, there were six partial responses and seven disease stabilizations with no complete responses. Median duration of response was 3 months (range, 2-7) and median survival was 5 months. Three patients developed grade 3-4 neutropenia, one patient had grade 3 anemia, four patients had grade 2-3 sensory neuropathy, and three patients had myalgias. Eighteen patients developed alopecia. Gastrointestinal toxicity was mild. One patient died after the first cycle due to pulmonary thrombo-embolism and could not be evaluated for response. The synergistic in vitro effect of the concurrent combination was confirmed in analyses performed under mutually exclusive and mutually nonexclusive criteria. In conclusion, the combination of methotrexate and paclitaxel at this dose and sequence is feasible and active as a palliative therapy in patients with advanced urothelial cancer previously treated with platinum-based therapies. This schedule merits further investigation in a phase-II trial.

Adenocarcinoma↗
PubMed2002

Capecitabine (Xeloda) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors.

OBJECTIVES: This phase I, dose-escalation study was conducted to determine the recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin. Secondary objectives included evaluation of the safety profile and antitumor activity. PATIENTS AND METHODS: Twenty-three patients with advanced or metastatic solid tumors received a 21-day regimen of oral capecitabine (500, 825, 1000 or 1250 mg/m2 twice daily, days 1-14) in combination with oxaliplatin (130 mg/m2, 2-h i.v. infusion, day 1). Dose-limiting toxicities were determined during the first treatment cycle, and safety and efficacy were evaluated throughout treatment. RESULTS: The recommended dosing schedule is oral capecitabine 1000 mg/m2 twice daily (days 1-14) with i.v. oxaliplatin 130 mg/m2 (day 1) in a 21-day treatment cycle. The principal dose-limiting toxicity was diarrhea. The most frequent treatment-related adverse events occurring during the study were gastrointestinal (nausea/vomiting, diarrhea) and neurological (dysesthesia, paresthesia). The majority of treatment-related adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 15 patients treated at or below the recommended dose. The most common grade 3/4 laboratory abnormalities were lymphocytopenia (52% of patients), thrombocytopenia (22%; grade 3 only), neutropenia (17%) and hyperbilirubinemia (17%). Among patients treated at or below the recommended dose level (n = 15), only two patients experienced grade 3 neutropenia and no patients experienced grade 4 neutropenia. Partial tumor responses occurred in six patients (26%), including five of nine patients (55%) with colorectal cancer. All responding patients were pretreated with 5-fluorouracil and four responders had received prior irinotecan. CONCLUSIONS: Oral capecitabine with i.v. oxaliplatin is a feasible combination regimen that shows promising antitumor activity in patients with colorectal cancer. There is an ongoing, phase II study to further characterize the safety and efficacy of this combination as first-line therapy for metastatic colorectal cancer, using the recommended dose identified in this study.

Administration, Oral↗