Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this s... more Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system...
Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in... more Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B(12) appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies.
GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical... more GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily p...
Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal c... more Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip® HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan® Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-ins...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2005
To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with l... more To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with locally advanced or metastatic non-small cell lung cancer. Patients were randomly assigned to receive pemetrexed 500 mg/m(2) plus oxaliplatin 120 mg/m(2) (PemOx) or pemetrexed plus carboplatin AUC6 (PemCb). All drugs were given on day 1 of a 21-day cycle for up to six cycles. Folic acid and vitamin B(12) were given to all patients to minimize pemetrexed-related toxicities. Forty-one patients received PemOx and 39 received PemCb. Objective tumor response rates were 26.8% for PemOx patients (95% confidence interval, 14.2-42.9) and 31.6% for PemCb patients (95% confidence interval, 17.5-48.7). Median time to progression was 5.5 and 5.7 months, respectively, for PemOx and PemCb. Median overall survival times were 10.5 months for both treatment groups (range, <1 to >20 months). The 1-year survival rate was 49.9% for PemOx patients and 43.9% for PemCb patients. Common toxicity criteria gr...
XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and st... more XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of this study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients received XR5000 at the dose
Objective: To demonstrate superior overall survival (OS) for the EGFR-targeted antibody cetuximab... more Objective: To demonstrate superior overall survival (OS) for the EGFR-targeted antibody cetuximab (Erbitux) in combination with CT compared to CT alone in the 1st-line treatment of advanced NSCLC. Methods: Pts with EGFR-expressing advanced NSCLC were randomized 1:1 to cetuximab (400 mg/m 2 initial dose, then 250 mg/m 2/wk) + CT (cisplatin 80 mg/m 2 d1 and vinorelbine 25 mg/m 2
Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) is involv... more Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) is involved in tumor development and progression in non-small-cell lung cancer (NSCLC). Somatic mutations in the EGFR kinase domain confer high sensitivity to tyrosine kinase inhibitors (TKIs). The two most frequent mutations are the exon 19 deletion and the exon 21 L858R. Distinct EGFR mutations differ in their effect on response and survival to TKIs. We have examined EGFR mutations in more than 1800 stage IV NSCLCs for erlotinib customization as both first- and second-line treatment. EGFR mutations cluster in never-smokers, women and adenocarcinomas, as has been described in multiple retrospective studies. The overall frequency of EGFR mutations in our study was 15% and the response in first- and second-line treatment was 84%. Overall, progression-free survival was 13 months and median survival has not been reached. However, patients with exon 19 deletions showed a significantly longer progression-free survival than those harboring L858R mutations. Despite abundant molecular evidence on the role of EGFR mutations, there is still no general agreement as to their predictive value. To clarify this important issue, the Spanish Lung Cancer Group has opened a Phase III trial comparing erlotinib with chemotherapy in stage IV NSCLC patients with EGFR mutations. This study is open to other European institutions.
Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a... more Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA). A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods. The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eigh...
Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this s... more Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system...
Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in... more Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B(12) appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies.
GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical... more GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily p...
Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal c... more Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip® HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan® Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-ins...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2005
To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with l... more To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with locally advanced or metastatic non-small cell lung cancer. Patients were randomly assigned to receive pemetrexed 500 mg/m(2) plus oxaliplatin 120 mg/m(2) (PemOx) or pemetrexed plus carboplatin AUC6 (PemCb). All drugs were given on day 1 of a 21-day cycle for up to six cycles. Folic acid and vitamin B(12) were given to all patients to minimize pemetrexed-related toxicities. Forty-one patients received PemOx and 39 received PemCb. Objective tumor response rates were 26.8% for PemOx patients (95% confidence interval, 14.2-42.9) and 31.6% for PemCb patients (95% confidence interval, 17.5-48.7). Median time to progression was 5.5 and 5.7 months, respectively, for PemOx and PemCb. Median overall survival times were 10.5 months for both treatment groups (range, <1 to >20 months). The 1-year survival rate was 49.9% for PemOx patients and 43.9% for PemCb patients. Common toxicity criteria gr...
XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and st... more XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of this study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients received XR5000 at the dose
Objective: To demonstrate superior overall survival (OS) for the EGFR-targeted antibody cetuximab... more Objective: To demonstrate superior overall survival (OS) for the EGFR-targeted antibody cetuximab (Erbitux) in combination with CT compared to CT alone in the 1st-line treatment of advanced NSCLC. Methods: Pts with EGFR-expressing advanced NSCLC were randomized 1:1 to cetuximab (400 mg/m 2 initial dose, then 250 mg/m 2/wk) + CT (cisplatin 80 mg/m 2 d1 and vinorelbine 25 mg/m 2
Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) is involv... more Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) is involved in tumor development and progression in non-small-cell lung cancer (NSCLC). Somatic mutations in the EGFR kinase domain confer high sensitivity to tyrosine kinase inhibitors (TKIs). The two most frequent mutations are the exon 19 deletion and the exon 21 L858R. Distinct EGFR mutations differ in their effect on response and survival to TKIs. We have examined EGFR mutations in more than 1800 stage IV NSCLCs for erlotinib customization as both first- and second-line treatment. EGFR mutations cluster in never-smokers, women and adenocarcinomas, as has been described in multiple retrospective studies. The overall frequency of EGFR mutations in our study was 15% and the response in first- and second-line treatment was 84%. Overall, progression-free survival was 13 months and median survival has not been reached. However, patients with exon 19 deletions showed a significantly longer progression-free survival than those harboring L858R mutations. Despite abundant molecular evidence on the role of EGFR mutations, there is still no general agreement as to their predictive value. To clarify this important issue, the Spanish Lung Cancer Group has opened a Phase III trial comparing erlotinib with chemotherapy in stage IV NSCLC patients with EGFR mutations. This study is open to other European institutions.
Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a... more Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA). A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods. The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eigh...
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Papers by Luis Paz-ares