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1.
Mol Cancer Ther ; 9(3): 751-60, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20197396

RESUMO

The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography-computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1-10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of >or=4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Biomarcadores Farmacológicos/análise , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Quinazolinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/farmacocinética , Biomarcadores Farmacológicos/metabolismo , Estudos de Coortes , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Piridinas/farmacocinética , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Sorafenibe , Resultado do Tratamento
2.
Clin Cancer Res ; 15(4): 1481-6, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19228749

RESUMO

PURPOSE: Cediranib is a potent oral inhibitor of the tyrosine kinase activity associated with all subtypes of vascular endothelial growth factor receptor. Purposes of this study were to determine the recommended phase II dose of cediranib in combination with standard doses of modified FOLFOX-6 (mFOLFOX-6), and the tolerability, safety, pharmacokinetics, and antitumor activity of this combination in patients with untreated metastatic colorectal cancer. EXPERIMENTAL DESIGN: Cediranib was administered daily orally at a starting dose of 30 mg and escalated to 45 mg daily, and mFOLFOX-6 was repeated every 14 days. Pharmacokinetic studies were done for oxaliplatin, 5-fluorouracil, and cediranib. Response was assessed by Response Evaluation Criteria in Solid Tumors every four cycles. RESULTS: Sixteen patients received 150 cycles of treatment (median, 6; range, 1-20 cycles). Of 9 patients enrolled at the 30-mg dose level, 1 patient experienced grade 3 diarrhea during cycle 1. No dose-limiting toxicity was observed in 7 patients at the 45-mg dose level. Common grade 3 toxicities related to cediranib included hypertension, diarrhea, fatigue, and anorexia. Of 14 patients evaluable for response, there were 6 partial responses (42.9%; 95% confidence interval, 17.7-71.1%) and 6 stable disease. The median progression-free survival was 9.3 months. There were no pharmacokinetic interactions between cediranib and 5-fluorouracil or free plasma intact oxaliplatin. CONCLUSIONS: Toxicities of this combination were manageable and consistent with previous studies. The recommended phase II dose is cediranib at 30 mg daily continuously in combination with standard doses of mFOLFOX-6. Cediranib and mFOLFOX-6 has promising antitumor activity and this combination warrants further investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Quinazolinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacocinética , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética
3.
Clin Cancer Res ; 14(11): 3450-5, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18519776

RESUMO

PURPOSE: Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that targets and activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4). Mapatumumab functions like the natural receptor ligand, TRAIL, a tumor necrosis factor superfamily member that is an important mediator of apoptosis in cancer cell lines. Promising preclinical activity with mapatumumab has been observed. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study assessed the tolerability and toxicity profile of > or =2 doses of mapatumumab administered i.v. in patients with advanced solid tumors. Patients received mapatumumab every 28 days until progression or dose-limiting toxicity. RESULTS: There were escalation levels from 0.01 to 20.0 mg/kg. Forty-one patients, 27 female, with a median age of 55 years (range, 23-81) were entered into the study and received 143 courses. The most common diagnoses were colorectal (10 patients) and ovarian cancer (9 patients). Patients received a median of two cycles (range, 1-33). Mapatumumab was well tolerated. Adverse events considered at least possibly related to mapatumumab that occurred most frequently included fatigue (36.2%), hypotension (34.1%), nausea (29.3%), and pyrexia (12.2%). The majority of adverse events were grade 1 or 2. The maximum tolerated dose was not reached. Linear pharmacokinetics was observed for doses up to 0.3 mg/kg and for the 20 mg/kg level, whereas exposure at 3 and 10 mg/kg increased less than proportionally. No objective responses were observed, but 12 patients had stable disease for 1.9 to 29.4 months. CONCLUSIONS: Mapatumumab is well tolerated and further evaluation of this TRAIL-R1 targeting agent is warranted.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade
4.
J Clin Oncol ; 26(12): 1940-7, 2008 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-18421048

RESUMO

PURPOSE: MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies. PATIENTS AND METHODS: A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs. RESULTS: Six dose levels ranging from 12.5 to 56 mg/m(2)/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m(2)/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m(2)/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103. CONCLUSION: At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.


Assuntos
Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Acetilação/efeitos dos fármacos , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Inibidores de Histona Desacetilases , Histonas/sangue , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/enzimologia , Neoplasias/metabolismo , Cooperação do Paciente , Pirimidinas/farmacocinética
5.
Clin Cancer Res ; 13(16): 4849-57, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17699864

RESUMO

PURPOSE: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. EXPERIMENTAL DESIGN: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. RESULTS: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. CONCLUSIONS: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Quinazolinas/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/farmacocinética , Receptores ErbB/fisiologia , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Piridinas/farmacocinética , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Sorafenibe
6.
Int J Radiat Oncol Biol Phys ; 67(4): 1027-36, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17197132

RESUMO

PURPOSE: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. METHODS AND MATERIALS: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m(2) gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m(2) within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m(2)) and 52.5 Gy RT within 6 weeks. RESULTS: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. CONCLUSION: Biweekly gemcitabine (40 mg/m(2)) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Radiossensibilizantes/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Dosagem Radioterapêutica , Análise de Sobrevida , Gencitabina
7.
Invest New Drugs ; 25(3): 217-25, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17146732

RESUMO

BACKGROUND: LY293111 is an oral agent known to be a leukotriene B4 (LTB4) receptor antagonist and a 5-lipoxygenase inhibitor resulting in selective inhibition of the lipoxygenase pathway. Lipoxygenases metabolize arachidonic acid and have been involved in cancer cell proliferation and survival. In addition, LY293111 has been found to be a peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist. Antineoplastic activity of LY293111 has been identified in preclinical models both alone and in combination with chemotherapy agents including irinotecan. The NCIC Clinical Trials Group studied LY293111 in combination with irinotecan to determine the recommended dose of the combination and to describe its tolerability and pharmacokinetic interaction. In addition the anti-tumour activity of LY293111 in combination with irinotecan was documented. PATIENTS AND METHODS: Twenty-eight patients with advanced solid tumours were treated on seven dose levels with the combination of irinotecan and LY293111. Irinotecan was administered intravenously every 21-days as a single dose. LY293111 was administered twice daily continuously by mouth. RESULTS: Dose limiting toxicity (DLT) of grade 3 diarrhea was seen in two patients with doses of irinotecan 300 mg/m(2) IV every 21-days in combination with LY293111 300 mg BID. Subsequently the dose of irinotecan was decreased to 250 mg/m(2) IV every 21-days with escalating doses of LY293111. A DLT of grade 3 abdominal pain was seen at dose 600 mg BID of LY293111 with irinotecan 250 mg/m(2). The pharmacokinetics (PK) indicated that the administration of LY293111 did not have an effect on the PK of irinotecan or its metabolite SN-38. No responses were seen; seven patients had stable disease of a median duration of 4.4 months (range 2.8-13 months). CONCLUSION: The recommended phase II dose of LY293111 is 600 mg orally BID in combination with irinotecan 250 mg/m(2) IV every 21-days. Gastrointestinal adverse effects were common but could be well managed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzoatos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Ontário , Fatores de Tempo , Resultado do Tratamento
8.
Support Care Cancer ; 15(7): 829-40, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17177040

RESUMO

GOALS OF WORK: The quality of informed consent in phase I trials is controversial, partially due to gaps in patient understanding. We assessed an educational DVD's impact on knowledge and satisfaction in cancer patients newly referred to a phase I clinic. MATERIALS AND METHODS: Forty-nine patients were randomly assigned to view an educational DVD (n = 22) which explained phase I trials or a placebo DVD (n = 27). Patients completed a questionnaire assessing knowledge of phase I studies and satisfaction with the DVD. The blinded interviewing physician (n = 8) rated the patient's understanding of phase I trials. MAIN RESULTS: The mean patient age was 56; 61% were male. Patients who viewed the educational DVD were less likely to believe that phase I trials determine drug efficacy (p = 0.019), more likely to know that phase I drugs have not been thoroughly studied in humans (p = 0.003), and less likely to believe that these agents have proven activity against human cancers (p = 0.008). More patients who viewed the educational DVD agreed/strongly agreed that the DVD provided useful information (p < 0.001), were confident in their knowledge of phase I trials (p = 0.031), felt aided in their decision to enter a phase I study (p = 0.011), and would have more questions for their physicians because of the DVD (p = 0.017). No statistically significant difference in physician perception of patient understanding or phase I trial accrual was observed between the educational and placebo DVD groups. CONCLUSIONS: An educational DVD increased patient knowledge and satisfaction regarding participation in phase I clinical trials.


Assuntos
Neoplasias/tratamento farmacológico , Educação de Pacientes como Assunto/métodos , Participação do Paciente , Avaliação de Programas e Projetos de Saúde , Gravação de Videoteipe , Antineoplásicos/uso terapêutico , Escolaridade , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Percepção
9.
BMC Cancer ; 6: 263, 2006 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-17092349

RESUMO

BACKGROUND: There is a paucity of literature on the referral outcome of patients seen in phase I trial clinics in academic oncology centres. This study aims to provide information on the accrual rate and to identify obstacles in the recruitment process. METHODS: A retrospective chart review was performed for all new patients referred and seen in the phase I clinic at the Princess Margaret Hospital between January 2000 and June 2005. Data on their demographics, medical history, and details of trial participation or non-entry were recorded. RESULTS: A total of 667 new phase I referrals were seen during the stated period. Of these patients, 197 (29.5%) patients were enrolled into a phase I trial, and 64.5% of them started trial within 1 month of the initial visit. About a quarter (165 of 667) of the patients referred were deemed ineligible at their first visit, with the most frequent reasons for ineligibility being poor performance status, unacceptable bloodwork, too many prior treatments and rapid disease progression. The remaining 305 patients (45.7%) were potentially eligible at their initial visit, but never entered a phase I trial. The main reasons for their non-entry were patient refusal, other treatment recommended first, and lack of available trials or trial spots. CONCLUSION: This study provides information on the clinical realities underlying a referral to a phase I clinic and eventual trial enrollment. Better selection of patients, appropriate education of referring physicians, and opening phase I trials with fewer restrictions on some criteria such as prior therapy may enhance their recruitment rates.


Assuntos
Ensaios Clínicos Fase I como Assunto , Definição da Elegibilidade , Neoplasias/terapia , Seleção de Pacientes , Centros Médicos Acadêmicos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta , Estudos Retrospectivos
10.
Invest New Drugs ; 23(5): 455-65, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16133797

RESUMO

Bay 38-3441 is a camptothecin glycoconjugate which stabilizes the active lactone form of camptothecin and allows selective uptake into tumor cells. We conducted a phase I study of Bay 38-3441 administered as a 30-minute infusion daily for five consecutive days every 21 days. Thirty-one patients were enrolled at 8 dose levels. Most common nonhematologic side effects were diarrhea (29%), vomiting (19%), nausea (19%), lethargy (13%), and abdominal pain (10%). The main hematologic toxicity was prolonged neutropenia. Nine patients had a best response of stable disease with a median duration of 2.7 months (range: 2.3-20.6 months). The study was closed without reaching the maximum tolerated dose (MTD) due to excessive toxicity in a companion trial resulting in termination of development of this agent. Bay 38-3441 was well tolerated in this study with granulocytopenia as the main hematologic toxicity. This study showed that glycoconjugation is a feasible delivery technique for camptothecin.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/análogos & derivados , Dipeptídeos/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Agranulocitose/induzido quimicamente , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Diarreia/induzido quimicamente , Dipeptídeos/efeitos adversos , Dipeptídeos/farmacocinética , Esquema de Medicação , Feminino , Glicoconjugados/administração & dosagem , Glicoconjugados/efeitos adversos , Glicoconjugados/farmacocinética , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo
11.
Cancer Chemother Pharmacol ; 56(2): 154-60, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15809877

RESUMO

BACKGROUND: Zosuquidar (LY335979) is an oral P-glycoprotein modulator. This phase I study was designed to determine the maximum tolerated dose (MTD) of zosuquidar in combination with vinorelbine. The effects of zosuquidar on vinorelbine pharmacokinetics were also examined. DESIGN: Patients with advanced solid tumours were treated with escalating doses of zosuquidar administered every 8-12 h on days 7-9 and 14-16 during cycle 1 then days 0-2, 7-9, and 14-16 from cycle 2 onwards, with vinorelbine 22.5-30 mg/m2 IV on days 1, 8 and 15 every 28 days. RESULTS: Of 21 patients registered, 19 were treated at four dose levels (zosuquidar 100-300 mg/m2). Two patients had prolonged and febrile neutropenia at the second dose level resulting in a reduction of the dose of vinorelbine in subsequent dose levels. There was another patient with dose-limiting febrile neutropenia at dose level four which resulted in the expansion of the dose level three. Eight patients had stable disease and no objective responses were seen. Vinorelbine pharmacokinetic studies showed reduced clearance when given with zosuquidar. CONCLUSIONS: The MTD was zosuquidar 300 mg/m2 orally every 12 h for 3 days weekly for 3 weeks with vinorelbine 22.5 mg/m2 IV weekly for 3 weeks every 28 days. Zosuquidar may inhibit vinorelbine clearance to a modest degree.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dibenzocicloeptenos/administração & dosagem , Dibenzocicloeptenos/efeitos adversos , Resistência a Múltiplos Medicamentos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Vimblastina/análogos & derivados , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Administração Oral , Adulto , Idoso , Dibenzocicloeptenos/farmacologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Quinolinas/farmacologia , Vimblastina/farmacologia , Vinorelbina
12.
Invest New Drugs ; 21(1): 85-97, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12795533

RESUMO

PURPOSE: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. PATIENTS AND METHODS: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. RESULTS: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m2/day. The dose level of 80 mg/m2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. CONCLUSIONS: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos/farmacologia , Oligonucleotídeos Antissenso/farmacologia , Adulto , Idoso , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferases/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Hemoglobina Fetal/análise , Humanos , Infusões Intravenosas , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/sangue , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/sangue , Proteínas/análise , Proteínas/genética , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/sangue , Tionucleotídeos , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Vimentina/sangue , Vimentina/genética , Proteínas GADD45
13.
J Clin Oncol ; 20(10): 2567-74, 2002 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-12011137

RESUMO

PURPOSE: Troxacitabine (Troxatyl, BCH-4556; BioChem Pharma Inc, Basingstoke, United Kingdom) is a novel synthetic L-nucleoside analog with activity against a broad range of human tumors in preclinical models. Preclinical toxicity suggested a predictable toxicity profile consistent with an agent of this class, with evidence of interspecies differences. We conducted a phase I study of troxacitabine given as a 30-minute infusion once every 21 days. PATIENTS AND METHODS: The starting dose of troxacitabine was 0.025 mg/m(2), based on toxicology data from the most sensitive species studied (cynomolgus monkey). Doses were doubled until grade 1 skin or mucosal or grade 2 other toxicity was encountered. A modified Fibonacci scale was used. RESULTS: A total of 45 patients were enrolled at 13 dose levels. Most common nonhematologic side effects were skin rash (44%), lethargy (29%), nausea (24%), alopecia, dry skin (18%), anorexia (13%), neurosensory symptoms (13%), and hand-foot syndrome (13%). In patients treated with prednisone 25 mg/d orally for 5 days, starting on day 1, skin rash was less problematic. Two patients at 12.5 mg/m(2) experienced dose-limiting (grade 4) granulocytopenia. Confirmed partial responses were documented in one patient with previously untreated renal cell carcinoma with metastatic lung and bone lesions and in one patient with an unknown primary tumor. Eighteen patients had a best response of stable disease with a median duration of 5.1 months (range, 2.1 to 18.7 months). CONCLUSION: When given in this schedule, the maximum-tolerated dose of troxacitabine is 12.5 mg/m(2), and the recommended dose for additional phase II studies is 10 mg/m(2) once every 21 days with steroid premedication.


Assuntos
Antineoplásicos/farmacocinética , Citosina/análogos & derivados , Citosina/farmacocinética , Dioxolanos/farmacocinética , Neoplasias/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Neoplasias/terapia , Trombocitopenia/induzido quimicamente , Distribuição Tecidual
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