RESUMEN
BACKGROUND: Pracinostat (SB939) is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDAC). The adult recommended phase II dose (RP2D) is 60 mg po three times per week (t.i.w.) for 3 weeks every 4 weeks. This study assessed the toxicities and pharmacokinetics of pracinostat and determined the RP2D in children with refractory solid tumors. METHODS: Pediatric patients with refractory solid tumors were treated with oral pracinostat t.i.w. for 3 consecutive weeks, followed by 1 week off dosing. Three dose levels-25, 35, and 45 mg/m(2) were evaluated using a standard 3 + 3 cohort design. Pharmacokinetic (PK) studies were optional. RESULTS: Twelve patients were enrolled. The most common diagnosis was Ewing sarcoma. Most adverse events (AEs) were hematological with five (40%) patients experiencing grade 3 neutropenia. Non-hematological AEs were generally grade 1. No dose limiting toxicities occurred. More hematological and non-hematological AEs occurred at 45 mg/m(2) : Two of five patients experienced Grade 3 neutropenia and one each Grade 3 thrombocytopenia and leucopenia, Grade 1 fatigue and anorexia occurred in three. The RP2D was declared to be 45 mg/m(2) (comparable to an adult dose of 80 mg). One patient had a best response of stable disease (duration of 2.9 months). Three patients on 25 mg/m(2) and one each on 35 and 45 mg/m(2) participated in the PK study. No dose related changes in Cmax or AUC occurred. CONCLUSIONS: Pracinostat is reasonably well tolerated in children with refractory solid tumors. The RP2D is 45 mg/m(2) .
Asunto(s)
Antineoplásicos/administración & dosificación , Bencimidazoles/administración & dosificación , Inhibidores de Histona Desacetilasas/administración & dosificación , Neoplasias/tratamiento farmacológico , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Lactante , Masculino , Dosis Máxima ToleradaRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacocinética , Citosina/análogos & derivados , Citosina/farmacocinética , Dioxolanos/farmacocinética , Neoplasias/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Neoplasias/terapia , Trombocitopenia/inducido químicamente , Distribución TisularRESUMEN
Hepatocellular carcinoma (HCC) remains a lethal treatment-resistant cancer with a median survival of <6 months in patients not considered candidates for radical surgical treatments. SB-715992 is a novel cytotoxic agent implicated in the inhibition of mitotic kinesin spindle protein (KSP). Based on evidence from preclinical models and phase I trials, we conducted a phase II trial of SB-715992 in chemo-naïve patients with advanced HCC. A non-randomized, non-blinded multicentre two-stage phase II study was completed examining the efficacy, toxicity, and pharmacokinetics of SB-715992 at 18 mg/m2 IV q 3 weeks, in patients with measurable locally advanced, metastatic or recurrent HCC. The predictive value of KSP in archival tumour was assessed. Fifteen patients with metastatic HCC received a median of 3 cycles of SB-715992. The most common grade 3+ toxicities were granulocytopenia, leukocytopenia, diarrhea and liver transaminase rise. Overall confirmed response rate was 0%. Seven (46%) patients had a best response of stable disease at the 8-week evaluation (median duration 3.9 months) Median time to progression was 1.61 months (95%CI = 1.31-3.94 months) SB-715992 plasma concentrations were comparable to those observed in the phase I studies. Expression of KSP by immunohistochemistry was observed in only four of eight evaluable samples with strong expression reported in only two. No correlation was observed between intensity of KSP staining and clinical outcome. Among these patients with preserved hepatic function and good performance status, SB-715992 was generally well tolerated. However, no conclusive evidence of benefit was seen with SB-715992 monotherapy in HCC.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Progresión de la Enfermedad , Femenino , Expresión Génica , Humanos , Infusiones Intravenosas , Cinesinas/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Resultado del TratamientoRESUMEN
To assess the response rate and toxicity of the kinesin spindle protein (KSP) inhibitor, ispinesib, in malignant melanoma. Seventeen patients were enrolled from April to November 2005. Ispinesib was administered as a 1-hour infusion at a dose of 18 mg/m2 once every 3 weeks until disease progression. No objective responses were seen. Six patients (35%) had a best response of stable disease for a median duration of 2.8 months. Disease progression was documented in 9 (53%) after 1 or 2 cycles. Eighty-eight percent of patients received > or =90% of planned dose intensity. Grade 3 non-hematologic toxicities included dizziness (1) and blurred vision (1). There was one episode of febrile neutropenia, but no grade 3 or 4 biochemical adverse events. Pharmacokinetics was consistent with prior studies. KSP immunoreactivity was seen in 14 of 16 available archival tissue samples (88%). Ispinesib can be safely administered using the dose and schedule employed, with mild hematologic and non-hematologic toxicity. No objective responses were observed, and further development of single-agent ispinesib in malignant melanoma is not recommended. Although KSP expression appears to be common in melanoma, KSP may not be a suitable target for its treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Neoplasias del Ojo/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Quinazolinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Progresión de la Enfermedad , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Cinesinas/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/patología , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Resultado del TratamientoRESUMEN
DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1-7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0-->inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Oligodesoxirribonucleótidos/uso terapéutico , Proteínas Represoras/antagonistas & inhibidores , Tionucleótidos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/metabolismo , Canadá , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/secundario , Femenino , Humanos , Neoplasias Renales/enzimología , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Oligodesoxirribonucleótidos/efectos adversos , Oligodesoxirribonucleótidos/metabolismo , ARN Mensajero/sangre , Tionucleótidos/efectos adversos , Tionucleótidos/metabolismoRESUMEN
PURPOSE: A multi-centre phase II study of SarCNU-a novel chloroethylnitrosourea (CNU)-in patients with recurrent malignant glioma to assess response rate, survival and effects of treatment. PATIENTS AND METHODS: Ten patients with histologically proven malignant glioma (seven with glioblastoma multiforme (GBM) and three with anaplastic astrocytoma) received SarCNU (860 mg/m(2)) orally on days 1, 5 and 9 on a 6 week schedule. RESULTS: A total of ten patients were treated on protocol before accrual was suspended for a high rate of pulmonary toxicity. Of eight evaluable patients, five demonstrated at least one grade deterioration in DLCO from baseline. This necessitated premature closure of the trial. Stable disease was seen in five of seven evaluable patients (median duration 4.8 months; range 0.8-9.2) with progressive disease in the remainder. CONCLUSION: Despite promising preclinical data, SarCNU caused pulmonary toxicity in patients with recurrent malignant glioma and we plan no further studies in this indication.
Asunto(s)
Antineoplásicos/uso terapéutico , Astrocitoma/tratamiento farmacológico , Carmustina/análogos & derivados , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Pulmón/efectos de los fármacos , Academias e Institutos , Adulto , Anciano , Antineoplásicos/efectos adversos , Canadá , Monóxido de Carbono/metabolismo , Carmustina/efectos adversos , Carmustina/uso terapéutico , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Capacidad de Difusión Pulmonar/efectos de los fármacosRESUMEN
PURPOSE: To assess the response rate and toxicity of the alkylphosphocholine analogue, perifosine, in patients with metastatic or recurrent malignant melanoma. PATIENTS AND METHODS: Patients had histologically proven, unidimensionally measurable disease which was incurable by standard therapy. Prior adjuvant immunotherapy was allowed but patients had not received prior chemotherapy. Perisfosine was given orally as a loading dose of 900 mg on day 1 followed by a maintenance dose of 150 mg po on days 2-21 in a 28 day cycle. The loading dose was 300 mg on day 1 of all subsequent cycles. Tumour response was assessed every 2 cycles. RESULTS: 18 patients were accrued over 7 mos. No objective responses occurred in the 14 evaluable patients. Three patients (21%) achieved stable disease after 2 cycles and 11 had progression. Seventeen patients were evaluable for toxicity. Grade 3 or 4 non-hematologic toxicities included: diarrhea (12%), arthralgia (12%), nausea (6%), headache (6%), and fatigue (6%). No grade 3 or 4 hematological or biochemical toxicity were observed. Seventy-seven percent of patients received >or=90% of planned cycle 1 dose intensity and 58% received >or=90% of planned dose for cycle 2+. Four patients required dose reductions; treatment was delayed in 5 patients; and 5 patients missed doses because of toxicity. CONCLUSIONS: Perifosine can be safely administered when given as an initial loading dose followed by daily maintenance therapy over 28 days. Gastrointestinal toxicity is common but generally of low grade. Hematological toxicity is minimal. No objective responses were observed. No further development of single-agent perifosine is recommended in malignant melanoma.
Asunto(s)
Melanoma/tratamiento farmacológico , Fosforilcolina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Artralgia/inducido químicamente , Condrocalcinosis/inducido químicamente , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Metástasis Linfática , Melanoma/secundario , Persona de Mediana Edad , Fosforilcolina/efectos adversos , Fosforilcolina/uso terapéuticoRESUMEN
OBJECTIVES: To determine the tolerability and efficacy of daily oral marimastat (BB-2516 in patients with metastatic melanoma and to determine the matrix metalloproteinase (MMP) activity, tumour necrosis, peri- and intra-tumoral fibrosis and tumor inflammation in pre- and post-treatment tumor biopsies. PATIENTS AND METHODS: Patients with measurable metastatic melanoma who had received no more than one prior chemotherapy regimen and lesions accessible for biopsy were eligible. The first 18 were treated with 100 mg p.o. twice daily and the next 11 received a reduced dose of 10 mg p.o. twice daily because of musculoskeletal toxicity. Response was assessed according to standard criteria. RESULTS: Twenty-nine patients were entered and 28 were eligible. Five had early progression (< 4 weeks of therapy), 2 experienced a partial responses persisting for 3.2 months and 3.6 months, 5 had stable disease and 16 progressive disease. Eleven patients had both pre- and post-treatment biopsies. In 3, no tumor tissue was present in one or the other biopsy. Two patients showed a clear increase in peri-tumoral fibrosis and two others showed an increase in tumor necrosis, but no consistent pattern in histologic changes was seen. In one patient, who later developed a PR, apoptosis was increased. CONCLUSION: Marimastat has only limited activity in patients with metastatic malignant melanoma. However, the observation of two partial responses was interesting given that this agent might have been expected to cause tumor stasis rather than regression. Additional studies will be required to determine if the development of peri-tumoral fibrosis or tumor necrosis antedates a clinical response to marimastat.
Asunto(s)
Ácidos Hidroxámicos/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos Antineoplásicos , Biopsia , Canadá , Femenino , Humanos , Masculino , Melanoma/enzimología , Metaloendopeptidasas/antagonistas & inhibidores , Persona de Mediana EdadRESUMEN
Fostriecin (CI-920) is a potent inhibitor of protein phosphatase 2A (PP2A) and protein phosphatase 4(PP4) found to have anticancer activity in preclinical testing. A phase I study was conducted to evaluate the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of this drug. Forty-six patients were treated with escalating doses of fostriecin (2-47 mg/m2) administered as a daily bolus infusion for five consecutive days. PK studies were performed at different time points following administration of fostriecin. Dose-limiting toxicities included: elevation of creatinine, bilirubin, and hepatic transaminases; nausea, anorexia, lethargy, and hypotension. PK studies were compatible with a two-compartment model. Regression analysis revealed a significant relationship between dose and clearance; however, the r2 value was only 0.168 indicating a low predictive value for the model. No significant difference was seen in PK parameters with repeated dosing during the same cycle. Although no tumor responses were seen, 16 patients had stable disease with a median duration response of 2.6 months. The study was closed before reaching MTD due to problems with the supply of fostriecin from the National Cancer Institute of the United States (NCI US). New methods for synthesizing fostriecin have recently been described and therefore further development of this unique anticancer agent may be warranted.
Asunto(s)
Alquenos/administración & dosificación , Alquenos/farmacocinética , Drogas en Investigación/farmacocinética , Adulto , Anciano , Alquenos/efectos adversos , Análisis de Varianza , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Drogas en Investigación/efectos adversos , Femenino , Estudios de Seguimiento , Enfermedades Gastrointestinales/sangre , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Inyecciones Intravenosas , Modelos Lineales , Masculino , Persona de Mediana Edad , Polienos , PironasRESUMEN
PURPOSE: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. PATIENTS AND METHODS: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. RESULTS: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. CONCLUSIONS: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.
Asunto(s)
Antineoplásicos/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Flavonoides/uso terapéutico , Melanoma/tratamiento farmacológico , Piperidinas/uso terapéutico , Adulto , Anciano , Anorexia/inducido químicamente , Antineoplásicos/efectos adversos , Diarrea/inducido químicamente , Fatiga/inducido químicamente , Femenino , Flavonoides/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Piperidinas/efectos adversos , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
To determine the efficacy and toxicity of a novel chemotherapeutic approach with topotecan, a camptothecin analog, for progressive or recurring anaplastic oligodendroglioma or mixed oligoastrocytoma.Patients from seven centers with recurrent or progressive disease were treated with topotecan, 1.5 mg/m(2) intravenously (i.v.), 30 min dailyx5 days every 3 weeks. Efficacy and toxicity were assessed clinically and radiologically. The study was planned to accrue up to 30 evaluable patients if there was at least one response among the first 15 patients treated. Sixteen eligible patients entered the study. No response was documented in 14 evaluable patients. Eleven patients had stable disease of a median of 3.8 months and three had progressive disease. Sixteen patients were evaluable for toxicity. The most significant toxic effect was myelosuppression. Grade 3 or 4 granulocytopenia was experienced by 15 of 16 patients and led to dose reduction in nearly half of the cycles delivered. Other adverse effects were fatigue, nausea, stomatitis, alopecia, and vomiting.Topotecan, delivered in the dailyx5 regimen, is relatively well tolerated. We could not demonstrate significant activity among the population studied to justify completing accrual to 30 patients. Topotecan did not demonstrate, with this small sample size, efficacy as a salvage chemotherapy monotherapy after exposure to procarbazine, CCNU and vincristine. Further trials with different agents in this indication are certainly warranted.
Asunto(s)
Astrocitoma/tratamiento farmacológico , Oligodendroglioma/tratamiento farmacológico , Topotecan/administración & dosificación , Astrocitoma/sangre , Fatiga/sangre , Fatiga/inducido químicamente , Humanos , Infusiones Intravenosas , Oligodendroglioma/sangre , Topotecan/efectos adversosRESUMEN
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.