RESUMO
PURPOSE: This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors. METHODS: A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and docetaxel was administered intravenously at 30 mg/m(2) for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles. RESULTS: Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel. CONCLUSION: The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxiglucose/administração & dosagem , Desoxiglucose/uso terapêutico , Neoplasias/tratamento farmacológico , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Glicemia/análise , Desoxiglucose/efeitos adversos , Docetaxel , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxoides/efeitos adversosRESUMO
PURPOSE: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. PATIENTS AND METHODS: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m² on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m² with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. RESULTS: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m². DLTs at 340 mg/m² were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. CONCLUSIONS: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.
Assuntos
Abscesso/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doxorrubicina/efeitos adversos , Dose Máxima Tolerável , Neutropenia/induzido quimicamente , Nitroimidazóis/efeitos adversos , Mostardas de Fosforamida/efeitos adversos , Sarcoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Celulite (Flegmão)/induzido quimicamente , Intervalo Livre de Doença , Doxorrubicina/análogos & derivados , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Toxidermias , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neutropenia/tratamento farmacológico , Nitroimidazóis/farmacocinética , Nitroimidazóis/uso terapêutico , Mostardas de Fosforamida/farmacocinética , Mostardas de Fosforamida/uso terapêutico , Sarcoma/cirurgia , Estomatite/induzido quimicamente , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The objectives of this phase 1, first-in-human study were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary activity of the hypoxia-activated prodrug TH-302 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TH-302 was administered intravenously over 30 to 60 minutes in two regimens: three times weekly dosing followed by 1 week off (arm A) and every 3-week dosing (arm B). RESULTS: Fifty-seven patients enrolled (arm A: N = 37 and arm B: N = 20). The TH-302 dose was escalated from 7.5 to 670 mg/m(2) in arm A and from 670 to 940 mg/m(2) in arm B. The most common adverse events were nausea, skin rash, fatigue, and vomiting. Hematologic toxicity was mild and limited. Grade 3 skin and mucosal toxicities were dose limiting at 670 mg/m(2) in arm A; the MTD was 575 mg/m(2). In arm B, grade 3 fatigue and grade 3 vaginitis/proctitis were dose limiting at 940 mg/m(2); the MTD was 670 mg/m(2). Plasma concentrations of TH-302 and the active metabolite Br-IPM (brominated version of isophosphoramide mustard) increased proportionally with dose. Two partial responses were noted in patients with metastatic small cell lung cancer (SCLC) and melanoma in arm A at 480 and 670 mg/m(2). Stable disease was observed in arms A and B in 18 and 9 patients, respectively. CONCLUSIONS: The MTD of TH-302 was 575 mg/m(2) weekly and 670 mg/m(2) every 3 weeks. Skin and mucosal toxicities were DLTs. On the basis of responses in metastatic melanoma and SCLC, further investigations in these indications were initiated.
Assuntos
Neoplasias/tratamento farmacológico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/farmacocinética , Nitroimidazóis/uso terapêutico , Mostardas de Fosforamida/efeitos adversos , Mostardas de Fosforamida/farmacocinética , Mostardas de Fosforamida/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/metabolismo , Neoplasias/patologia , Nitroimidazóis/administração & dosagem , Mostardas de Fosforamida/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêuticoRESUMO
PURPOSE: The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial. EXPERIMENTAL DESIGN: In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta-like ligand (Dll) 4, Bv8, p53 and thymidine phosphorylase) on formalin-fixed, paraffin-embedded tissue. PFS was associated with these variables in retrospective subset analyses. RESULTS: Patients with low scores for Dll4, VEGF-C, and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (P values = 0.01, 0.05, and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing. CONCLUSION: These retrospective subset analyses suggest that expression of Dll4, VEGF-C, and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Bevacizumab , Neoplasias da Mama/patologia , Capecitabina , Ensaios Clínicos Fase III como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Neuropilina-1 , Fator C de Crescimento do Endotélio VascularRESUMO
OBJECTIVES: A dose-escalation study of glufosfamide plus gemcitabine showed that the combination could be administered safely at full doses. The purpose of this phase II study was to evaluate the safety and efficacy of this combination in chemotherapy-naive pancreatic adenocarcinoma. METHODS: Eligible patients had metastatic and/or locally advanced pancreatic adenocarcinoma, Karnofsky performance status >or=70, creatinine clearance (CrCL) >or=60 mL/min, and acceptable organ function. Patients received glufosfamide 4500 mg/m intravenous on day 1 and gemcitabine 1000 mg/m intravenous on Days 1, 8, and 15 of every 28-day cycle. The primary end point was response rate. RESULTS: Twenty-nine patients were enrolled; 14 male, median age 58 years. Twenty-three (79%) patients had distant metastases. Median cycles on treatment was 4 (range: 1-18+). Of 28, 5 (18%; 95% CI: 6%-37%) patients had a confirmed partial response (median duration: 8.4 months) and 1 had an unconfirmed partial response. Eleven patients (39%) had stable disease. Median progression-free survival was 3.7 months, median overall survival was 6 months, and 1-year survival was 32%. Grade 3/4 neutropenia occurred in 23 (79%) patients and grade 3/4 thrombocytopenia in 10 (34%) patients. The CrCL fell below 60 mL/min in 10 of 27 (37%) patients. Renal failure occurred in 4 patients. Decrease in CrCL was correlated with glufosfamide and isophosphoramide mustard pharmacokinetic area under the curve. CONCLUSIONS: The combination of glufosfamide plus gemcitabine is active in pancreatic cancer; however, hematologic and renal toxicity were pronounced. Alternative dosing of glufosfamide plus gemcitabine should be explored.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Glucose/análogos & derivados , Humanos , Ifosfamida/análogos & derivados , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Mostardas de Fosforamida/administração & dosagem , Segurança , Taxa de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: There are currently no approved therapies for patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine. This Phase III trial evaluated the efficacy and safety of glufosfamide as compared with best supportive care (BSC) in this patient population. METHODS: Patients were randomised to glufosfamide plus BSC or to BSC alone with baseline performance status as a stratification factor. The primary end-point was overall survival. RESULTS: Three hundred and three patients were randomised: 148 to glufosfamide plus BSC and 155 to BSC alone. There was an 18% increase in overall survival for glufosfamide that was not statistically significant: hazard ratio (HR) 0.85 (95% confidence interval (CI) 0.66-1.08, p=0.19). Median survival was 105 (range 5-875) days for glufosfamide and 84 (range 2+ to 761) days for BSC. Grade 3/4 creatinine increase occurred in 6 patients on glufosfamide, including 4 with dosing errors. CONCLUSION: These results suggest low activity of glufosfamide in this very refractory patient population.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Mostardas de Fosforamida/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Glucose/análogos & derivados , Humanos , Ifosfamida/análogos & derivados , Masculino , Pessoa de Meia-Idade , Mostardas de Fosforamida/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: To evaluate safety and pharmacokinetics and to establish the maximum tolerated dose of glufosfamide when administered in combination with gemcitabine in advanced solid tumors. METHODS: This Phase 1 dose-escalation study evaluated the combination of glufosfamide + gemcitabine in patients with advanced solid tumors. Cohorts of three to six patients were treated with glufosfamide doses from 1,500 to 4,500 mg/m(2) i.v. over 4 h on Day 1 and gemcitabine 1,000 mg/m(2) i.v. over 30 min on Days 1, 8 and 15 of every 28-day cycle. Detailed PK sampling was performed on days 1 and 8 of the first two cycles. RESULTS: Nineteen patients were enrolled. Two patients had dose-limiting toxicity: Grade 3 fatigue at 2,500 mg/m(2) and Grade 4 thrombocytopenia at 4,500 mg/m(2). Five patients completed six cycles and one patient remained on study for ten cycles. Two patients discontinued for adverse events. Grade 3/4 neutropenia and thrombocytopenia occurred in seven patients and five patients, respectively. The CrCL fell below 60 mL/min in two patients. There was one unconfirmed partial response and 10 of 19 (52.6%) patients had stable disease or better at 8 weeks and three patients had continuing stable disease at 24 weeks. Pharmacokinetic analyses suggest no interaction between glufosfamide and gemcitabine. CONCLUSION: Phase I data indicate that full dose glufosfamide (4,500 mg/m(2)) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Glucose/análogos & derivados , Meia-Vida , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Humanos , Ifosfamida/análogos & derivados , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Mostardas de Fosforamida/administração & dosagem , GencitabinaRESUMO
Vascular endothelial growth factor promotes angiogenesis, an important mediator of growth and metastasis in human breast cancer. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, is under investigation as an anti-angiogenic agent. This phase I/II trial evaluated the safety and efficacy of bevacizumab in patients with previously treated metastatic breast cancer. Seventy-five patients were treated with escalating doses of bevacizumab ranging from 3 mg/kg to 20 mg/kg administered intravenously every other week. Tumor response was assessed before the sixth (70 days) and 12th (154 days) doses. Safety was evaluated during every cycle. Eighteen patients were treated at 3 mg/kg, 41 at 10 mg/kg, and 16 at 20 mg/kg. Four patients discontinued study treatment because of an adverse event. Hypertension was reported as an adverse event in 17 patients (22%). The overall response rate was 9.3% (confirmed response rate, 6.7%). The median duration of confirmed response was 5.5 months (range, 2.3 to 13.7 months). At the final tumor assessment on day 154, 12 of 75 patients (16%) had stable disease or an ongoing response. The optimal dose of bevacizumab in this trial was 10 mg/kg every other week and toxicity was acceptable. These data support the initiation of trials in metastatic breast cancer combining bevacizumab with chemotherapy.