RESUMO
The purine analog 2',3'-dideoxyinosine (ddI), which has anti-retroviral activity in vitro was administered for up to 42 weeks to 26 patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex (ARC). Ten of these individuals were AZT-intolerant. Eight dose regimens were studied. The drug was orally bioavailable and penetrated into the cerebrospinal fluid (CSF). Comparatively little evidence of an effect against human immunodeficiency virus (HIV) was seen at the lowest four doses. However, patients in the four highest dose groups (ddI at 1.6 milligrams per kilogram intravenously and then greater than or equal to 3.2 milligrams per kilogram orally at least every 12 hours or higher) had increases in their circulating CD4+ T cells (P less than 0.0005), increased CD4/CD8 T cell ratios (P less than 0.01), and, where evaluable, more than an 80% decrease in serum HIV p24 antigen (P less than 0.05). The patients also had evidence of improved immunologic function, had reduced viremic symptomatology, and gained a mean of 1.6 kilogram with these comparatively infrequent dosing schedules (every 8 or 12 hours). The most notable adverse effects directly attributable to ddI administration at the doses used in this study included increases in serum uric acid (due to hypoxanthine release) and mild headaches and insomnia. These results suggest that serious short-term toxicity at therapeutic doses is not an inherent feature in the profile of agents with clinical anti-HIV activity. Further controlled studies to define the safety and efficacy of this agent may be worth considering.
Assuntos
Complexo Relacionado com a AIDS/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Antivirais/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , HIV/efeitos dos fármacos , Complexo Relacionado com a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Antivirais/efeitos adversos , Antivirais/líquido cefalorraquidiano , Antivirais/farmacologia , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Didanosina , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/líquido cefalorraquidiano , Didesoxinucleosídeos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Antígenos HIV/análise , Proteína do Núcleo p24 do HIV , Humanos , Hipersensibilidade Tardia , Imunidade Celular , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Proteínas dos Retroviridae/análise , Linfócitos T/imunologiaRESUMO
Advances in antiretroviral therapy and treatment or prophylaxis against opportunistic infection have resulted in prolongation of the survival of patients with acquired immunodeficiency syndrome (AIDS). Previous research has demonstrated an association between AIDS and risk of non-Hodgkin's lymphoma (NHL). In addition to the approximately 3% of individuals found to have NHL at the time of AIDS onset, others continue to develop NHL following AIDS diagnosis. Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute demonstrated a sharply increasing incidence of NHL among men in the age range 20-49 years since 1983 in the United States. Based on new data on the risk of NHL following AIDS diagnosis, on estimates of improved survival following AIDS diagnosis, and on projections of future AIDS incidence, we considered four sets of assumptions and estimated the number of AIDS-related NHL cases in 1992 to be between 2900 and 9800. Three of these projections were higher than the estimate of 4700 cases obtained by linear extrapolation of SEER incidence trends. These projections of AIDS-related NHL incidence suggest that between 8% and 27% of all NHL cases that occur in the United States in 1992 will arise as a consequence of infection with the human immunodeficiency virus (HIV), imposing a substantial health care burden. More research into the pathogenesis of lymphoma and new approaches to antiretroviral and antilymphoma therapy will be necessary to prevent and treat this formidable complication of infection with HIV.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Linfoma não Hodgkin/epidemiologia , Síndrome da Imunodeficiência Adquirida/epidemiologia , Adulto , Feminino , Previsões , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Incidência , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/etiologia , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
BACKGROUND: Neovascularization induced by basic fibroblast growth factor (basic FGF) or FGF-like cytokines is thought to play a substantial role in the pathogenesis of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma. Pentosan polysulfate has been shown to inhibit basic FGF and FGF-like dependent tumor growth both in vitro and in vivo. Moreover, it has been found to inhibit the growth of Kaposi's sarcoma-derived spindle cells in vitro. These observations suggested that pentosan polysulfate might be worth exploring as a potential agent for the treatment of Kaposi's sarcoma. PURPOSE: The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose of pentosan polysulfate in patients with HIV-associated Kaposi's sarcoma and whether or not this compound had activity against this neoplasm. METHODS: Sixteen HIV-seropositive patients with Kaposi's sarcoma received pentosan polysulfate via continuous venous infusion for 3-6 weeks and then received a subcutaneous dose three times per week. Three different doses of pentosan polysulfate were administered: 2 mg/kg per day by infusion followed by 2 mg/kg per dose given subcutaneously (six patients), 3 mg/kg per day by infusion followed by 3 mg/kg per dose given subcutaneously (five patients), and 4 mg/kg per day by infusion followed by 4 mg/kg per dose given subcutaneously (five patients). Five of the 16 patients in the study also received injections of 1 mg of pentosan polysulfate into two different lesions two times a week for 3 weeks, followed by intralesional therapy once weekly. After receiving pentosan polysulfate for 6 weeks, patients were administered 100 mg zidovudine (AZT) orally every 4 hours in conjunction with pentosan polysulfate. RESULTS: The maximally tolerated dose of pentosan polysulfate given by continuous venous infusion was found to be 3 mg/kg per day. No patient had an objective clinical antitumor response to either systemic or intralesional pentosan polysulfate administration; however, three patients had stable Kaposi's sarcoma for 3-27 weeks. No statistically significant effect on CD4 cells or serum HIV p24 antigen was noted during pentosan polysulfate administration. Dose-limiting toxic effects were characterized by anticoagulation and thrombocytopenia and were reversible. CONCLUSION: Pentosan polysulfate was well tolerated in this patient population. However, no objective tumor response or evidence of anti-HIV activity was noted; therefore, no claim of activity can be made in this trial. IMPLICATION: Continued investigation into the use of angiogenesis inhibitors with improved activity and toxicity profiles or different mechanisms of action is warranted.
Assuntos
Soropositividade para HIV/complicações , Poliéster Sulfúrico de Pentosana/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , HIV/efeitos dos fármacos , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Poliéster Sulfúrico de Pentosana/farmacocinética , Sarcoma de Kaposi/etiologiaRESUMO
Early phase evaluation of anticancer drugs has traditionally used toxicity (usually hematological) rather than efficacy end points to establish appropriate dosing schedules. To establish a biochemical efficacy end point for overcoming alkylguanine DNA alkyltransferase (AGT)-mediated tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea, we performed a novel dose escalation clinical trial for the AGT-depleting agent O6-benzylguanine (BG). The dose of BG required to deplete AGT to undetectable levels (BMD(T)) in sequential computed tomography-guided tumor tissue biopsies before BG and 18 h after BG was determined. Thirty patients received doses of BG ranging from 10 to 120 mg/m2. In tumor tissue, AGT depletion >86% of baseline was demonstrated at all doses tested. Residual tumor AGT activity, present 18 h after BG doses of 10-80 mg/m2, was eliminated at the 120 mg/m2 dose and is thus the BMD(T) of BG. BG pharmacokinetics are characterized by the rapid, dose-independent clearance of BG from plasma Metabolism of BG to its biologically active metabolite, 8-oxo-benzylguanine (8-oxo-BG), was found. The t(1/2) of 8-oxo-BG is longer than BG. Plasma concentrations of 8-oxo-BG well above 200 ng/ml 18 h after the end of the BG infusion were observed at the highest dose levels tested and appeared to correlate with depletion of AGT activity to undetectable levels in tumor tissue. AGT activity in peripheral blood mononuclear cells at baseline did not correlate with tumor tissue AGT activity. Depletion of AGT activity to undetectable levels in peripheral blood mononuclear cells occurred at lower doses and was not a reliable predictor for tumor tissue depletion. No serious side effects were observed with administration of BG alone or in combination with 13 mg/m2 1,3-bis(2-chloroethyl)-1-nitrosourea. This is the first clinical study in which biochemical analyses from pre- and posttreatment tumor biopsies have been used as an efficacy end point for the clinical development of an anticancer agent. From our tumor tissue biopsy data, we have established that a BG dose of 120 mg/m2 infused over 1 h should be used in Phase II clinical trials.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Carmustina/farmacologia , Reparo do DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos , Guanina/análogos & derivados , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , O(6)-Metilguanina-DNA Metiltransferase/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/uso terapêutico , Biópsia , Biotransformação , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Carmustina/farmacocinética , Carmustina/uso terapêutico , Neoplasias do Sistema Digestório/sangue , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/enzimologia , Neoplasias do Sistema Digestório/patologia , Feminino , Guanina/efeitos adversos , Guanina/biossíntese , Guanina/farmacocinética , Guanina/uso terapêutico , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/enzimologia , Neoplasias/patologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Segurança , Tomografia Computadorizada por Raios XRESUMO
Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such cytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be just as effective as higher doses, implying that toxicity may not be an ideal end point for dose finding. Because of these factors, the sequence and design of traditional phase I, II, and III trials used for cytotoxic agents (which typically shrink tumors and in a dose-dependent manner) may not be appropriate for cytostatic agents. This article discusses options for modifying trial designs to accommodate cytostatic agents. Examples are given where these options have been tried or are currently being tried. Recommendations given for choosing among the trial designs depend on what is known preclinically about the agents (eg, does one have a validated and reproducible biologic end point that can be used to guide a dose escalation?), what is known about the patient population being studied (eg, does one have a well-documented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patients available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches.
Assuntos
Antineoplásicos , Avaliação de Medicamentos/métodos , Projetos de Pesquisa , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , Tamanho da AmostraRESUMO
PURPOSE: A phase I/II study of oral all-trans-retinoic acid (ATRA; tretinoin), administered every other week alone and then in combination with interferon (IFN) alfa-2a, was undertaken to evaluate the activity, toxicity, and pharmacokinetics of this regimen in patients with human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS). PATIENTS AND METHODS: Thirteen patients with HIV-associated KS, eight of whom had more than 100 CD4 cells/microL, were entered. The protocol initially called for patients to receive 150 mg/m2/d of ATRA every other week. However, this regimen was associated with headaches, and the initial dose of ATRA was reduced to 40 mg/m2/d orally in three divided doses, increasing to a maximum of 100 mg/m2/d. After 12 weeks, IFN alfa-2a could be added. RESULTS: The principal toxicities from ATRA were headaches (12 patients) and dry skin or lip (seven patients). Of 12 assessable patients, 10 had progressive disease and two had stable disease on ATRA alone. One of eight assessable patients who went on to receive ATRA plus IFN alfa-2a had partial response (PR). There were no overall changes in the serum HIV p24 antigen (Ag) level or CD4 count during treatment with ATRA alone. Peak ATRA levels decreased during the week of continuous ATRA therapy, but rebounded when treatment was resumed after a week without the drug. CONCLUSION: Intermittent ATRA therapy was reasonably well tolerated and provided a means to circumvent the low plasma exposure found with continuous ATRA therapy. However, we were unable to document antitumor activity in patients with HIV-associated KS.
Assuntos
Interferon-alfa/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Tretinoína/administração & dosagem , Adulto , Terapia Combinada , Esquema de Medicação , HIV/efeitos dos fármacos , HIV/fisiologia , Infecções por HIV/complicações , Cefaleia/induzido quimicamente , Humanos , Interferon alfa-2 , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Análise de Regressão , Indução de Remissão , Sarcoma de Kaposi/etiologia , Sarcoma de Kaposi/terapia , Sarcoma de Kaposi/virologia , Tretinoína/efeitos adversos , Tretinoína/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
PURPOSE: Administration of all-trans-retinoic acid (ATRA) on a continuous daily schedule results in a rapid and sustained decrease in plasma drug concentrations. This pharmacokinetic study was performed to determine if administration of ATRA on an intermittent schedule could overcome the rapid decrease in plasma drug concentration and provide repetitive periods of higher plasma drug exposure. MATERIALS AND METHODS: ATRA was administered on repetitive cycles of 7 consecutive days of drug followed by 7 days without drug. On the days of pharmacokinetic monitoring, following an overnight fast, a fixed single oral dose of 40 mg/m2 was administered and frequent plasma samples were obtained over 8 hours. Patients had pharmacokinetic studies performed on the first and seventh days of the first week, and on the first day of the third and eleventh weeks. ATRA was measured in plasma with a reverse-phase high-performance liquid chromatography (HPLC) assay. RESULTS: Plasma exposure to ATRA as measured by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from a mean of 145 +/- 26 mumol/L.min on day 1 to 18 +/- 4 mumol/L.min by day 7. Plasma ATRA concentrations at the start of weeks 3 and 11 of this every-other-week schedule were equivalent to those achieved on day 1 of treatment, with mean AUCs of 177 +/- 39 and 128 +/- 30 mumol/L.min, respectively. CONCLUSION: An intermittent schedule of ATRA administration results in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment. Phase II trials to evaluate the role of intermittent schedules of administration for ATRA are planned.
Assuntos
Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/farmacocinética , Síndrome da Imunodeficiência Adquirida/complicações , Adulto , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Esquema de Medicação , Tolerância a Medicamentos , Meia-Vida , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/etiologia , Pessoa de Meia-Idade , Indução de Remissão , Sarcoma de Kaposi/complicações , Tretinoína/administração & dosagem , Tretinoína/sangue , Regulação para CimaRESUMO
PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Inibidores de Metaloproteinases de Matriz , Neoplasias/tratamento farmacológico , Tetraciclinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/farmacocinética , Fatores de Crescimento Endotelial/sangue , Inibidores Enzimáticos/farmacocinética , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Linfocinas/sangue , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Tetraciclinas/farmacocinética , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
PURPOSE: To investigate the occurrence of non-Hodgkin's lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy and factors associated with the development of these lymphomas. PATIENTS AND METHODS: The charts of 55 patients with advanced HIV infection receiving zidovudine (formerly known as azidothymidine [AZT])-based therapy and 61 patients receiving dideoxyinosine (ddI) were examined for the occurrence of NHL. Stored samples from the AZT-based treatment cohort were examined retrospectively for parameters predictive of the subsequent development of lymphoma. RESULTS: Eight of 55 patients receiving AZT-based therapy developed NHL, yielding an estimated probability of 12% (95% confidence interval [CI], 4.7% to 27.1%) after 24 months, and 29.2% (95% CI, 15.2% to 48.7%) after 36 months. Four of 61 patients receiving ddI developed NHL, yielding a 6.2% (95% CI, 2.1% to 17%) estimated probability after 24 months, and 9.5% (95% CI, 3.6% to 22.8%) after 36 months. The difference between these cohorts was not significant (two-tailed P [P2] = .13). Patients with less than 50 CD4 cells/microL developed NHL at a significantly higher rate (P2 = .0085). This was particularly true for patients who presented with primary CNS lymphoma (PCNSL). For patients receiving AZT-based therapy, pretreatment serum interleukin-6 (IL-6) levels were somewhat higher in those who subsequently developed NHL than in those who did not (P2 = .048). CONCLUSION: HIV-infected patients with profound immunodeficiency, especially those with less than 50 CD4 cells/microL, are at substantial risk of developing NHL and particularly PCNSL. Additional studies are needed to define the role of other factors such as IL-6 in the pathogenesis of these opportunistic tumors.
Assuntos
Didanosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Linfoma Relacionado a AIDS , Linfoma não Hodgkin/etiologia , Zidovudina/uso terapêutico , Linfócitos T CD4-Positivos , Didanosina/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Interleucina-6/sangue , Contagem de Leucócitos , Linfoma Relacionado a AIDS/imunologia , Fatores de Risco , Zidovudina/efeitos adversosRESUMO
PURPOSE: To assess the toxicity and activity of oral thalidomide in Kaposi's sarcoma (KS) in a phase II dose-escalation study. PATIENTS AND METHODS: Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. RESULTS: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. CONCLUSION: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Fármacos Anti-HIV/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Talidomida/uso terapêutico , Administração Oral , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/patologia , Talidomida/administração & dosagem , Talidomida/efeitos adversosRESUMO
PURPOSE: To define, in a phase I study in relapsed non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), the maximum-tolerated dose (MTD), major toxicities, and possible antitumor activity of bryostatin 1, a macrocyclic lactone. PATIENTS AND METHODS: Bryostatin 1 was delivered by 72-hour continuous infusion every 2 weeks to patients with relapsed NHL or CLL, at doses that ranged from 12 microg/m2 to 180 microg/m2 per course. Correlative investigations included evaluations of total protein kinase C (PKC) in peripheral blood and lymphoid differentiation in patient tumor tissue. RESULTS: Twenty-nine patients were treated, including three patients with CLL and 26 with NHL. Generalized myalgia was the dose-limiting toxicity (DLT) and occurred in two of three patients treated with bryostatin 1 at 180 microg/m2 per course. Myalgias were dose-related and cumulative, and often started in the thighs and calves, improved with activity, were somewhat responsive to analgesics, and often took weeks to resolve once taken off study. Six patients were treated at the MTD of 120 microg/m2 per course. Myalgia, headache, and fatigue were common. Hematologic toxicity was uncommon. Total cumulative doses of bryostatin 1 up to 1,134 microg/m2 have been administered without untoward toxicity. Eleven patients achieved stable disease for 2 to 19 months. An in vitro assay for total PKC evaluation in patient peripheral-blood samples demonstrated activation within the first 2 hours with subsequent downregulation by 24 hours, which was maintained throughout the duration of the 72-hour infusion. CONCLUSION: This phase I study defined the MTD and recommended phase II dose of bryostatin 1, when administered over 72 hours every 2 weeks, to be 120 microg/m2 (40 microg/m2/d for 3 days). Generalized myalgia was the DLT. Future studies will define the precise activity of bryostatin 1 in subsets of patients with lymphoproliferative malignancies and its efficacy in combination with other agents.
Assuntos
Antineoplásicos/administração & dosagem , Lactonas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Antígenos CD/metabolismo , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Briostatinas , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactonas/efeitos adversos , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma não Hodgkin/metabolismo , Macrolídeos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Dor/induzido quimicamente , RecidivaRESUMO
PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Supratentoriais/tratamento farmacológico , Talidomida/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Biomarcadores Tumorais/sangue , Quimioterapia Adjuvante , Terapia Combinada , Constipação Intestinal/induzido quimicamente , Progressão da Doença , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Seguimentos , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Glioma/radioterapia , Humanos , Hipnóticos e Sedativos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Indução de Remissão , Neoplasias Supratentoriais/radioterapia , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversosRESUMO
PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O6-position of guanine. O6-benzylguanine (O6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial to define the presurgical dose required for depletion of tumor AGT activity in patients with malignant glioma. MATERIALS AND METHODS: Patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m2 given over 1 hour. Resected tumor was snap-frozen in liquid nitrogen and AGT activity analyzed by high-pressure liquid chromatography (HPLC). Up to 13 patients were treated at a specific dose of O6-BG, with a target end point of > or = 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein). RESULTS: Thirty patients with malignant gliomas were enrolled, with 11 of 11 patients treated at 100 mg/m2 O6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated. CONCLUSION: These results indicate that 100 mg/m2 of O6-BG can maintain tumor AGT levels less than 10 fmol/mg protein for at least 18 hours after treatment, a time interval in which bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully converted into interstrand cross-links. A 100-mg/m2 dose of O6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU.
Assuntos
Neoplasias Encefálicas/cirurgia , Inibidores Enzimáticos/administração & dosagem , Glioblastoma/cirurgia , Guanina/análogos & derivados , Adulto , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Guanina/administração & dosagem , Humanos , Pessoa de Meia-Idade , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Cuidados Pré-OperatóriosRESUMO
PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Talidomida/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Esquema de Medicação , Fatores de Crescimento Endotelial/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Substâncias de Crescimento/metabolismo , Humanos , Linfocinas/metabolismo , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Talidomida/administração & dosagem , Talidomida/farmacocinética , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
PURPOSE: To investigate the antitumor activity and safety of paclitaxel in patients with advanced human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS). PATIENTS AND METHODS: Twenty-nine patients with advanced HIV-associated KS were enrolled. The patients were overall quite immunosuppressed (median CD4 count, 15 cells/microL). Paclitaxel was initially administered at 135 mg/m2 over 3 hours every 3 weeks without filgrastim support; the dose was increased as tolerated to a maximum of 175 mg/m2. Patients who failed to respond or progressed could then receive filgrastim support or paclitaxel administered over 96 hours. RESULTS: Of 28 assessable patients, 20 had major responses (18 partial responses [PRs], one clinical complete response [CR], and one CR), for a major response rate of 71.4% (95% confidence interval [CI], 51.3% to 86.8%). Each of the five patients with pulmonary KS responded, as did all four assessable patients who had previously received anthracycline therapy for KS. Of six patients who went on to receive a 96-hour infusion of paclitaxel, five had major responses. Neutropenia was the most frequent dose-limiting toxicity; possible novel toxicities included late fevers, late rash, and eosinophilia. Two patients developed an elevated creatinine concentration and one cardiomyopathy. CONCLUSION: Paclitaxel has substantial activity against advanced HIV-associated KS as a single agent, even in patients with pulmonary involvement or who had previously received anthracyclines. Further research is needed to define the optimal treatment schedule and its role vis-a-vis the other available therapies for this disease.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Paclitaxel/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/complicações , Adulto , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Esquema de Medicação , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Probabilidade , Proteínas Recombinantes , Indução de Remissão , Sarcoma de Kaposi/etiologia , Análise de SobrevidaRESUMO
PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Astrocitoma/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Guanina/análogos & derivados , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Astrocitoma/sangue , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Carmustina/farmacocinética , Neoplasias do Sistema Nervoso Central/sangue , Esquema de Medicação , Glioblastoma/sangue , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/sangue , Guanina/farmacocinética , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
PURPOSE: Preclinical and clinical investigation of the combination of the antiangiogenesis/anti-invasion agent carboxyamido-triazole (CAI) administered with the cytotoxic agent paclitaxel (PAX). EXPERIMENTAL DESIGN: Colony-forming assays were used to test the activity of CAI plus PAX on A2780 human ovarian cancer. The sequence of CAI followed by PAX (CAI>Pax) was modeled in nude mice to test for potential additive toxicity. The Phase I clinical dose escalation schema tested p.o. administered CAI in PEG-400 (50-100 mg/m(2)) or micronized CAI (250 mg/m(2)) for 8 days followed by a 3-h infusion of PAX (110-250 mg/m(2)) every 21 days. Patients were assessed for toxicity, pharmacokinetics of CAI and PAX, and disease outcome. RESULTS: In preclinical studies, CAI>Pax was additive in A2780 human ovarian cancer cell lines when CAI (1 or 5 microM) preceded subtherapeutic doses of PAX. CAI did not reverse PAX resistance and collateral resistance to CAI was documented in PAX-resistant cells. CAI>PAX administration had no overt additive toxicity in nude mice. Thirty-nine patients were treated on a dose-escalation Phase I trial using daily oral CAI for 8 days followed by the PAX infusion. Pharmacokinetic analysis revealed that PAX caused an acute increase in circulating CAI concentrations in a dose-dependent fashion. No additive or cumulative toxicity was observed, and grade 3 nonhematological toxicity was rare. Three partial responses and two minor responses were observed. CONCLUSIONS: The sequential combination of CAI and PAX is well tolerated, and the activity observed suggests that further study of the combination is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interações Medicamentosas , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Recidiva , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Adulto , Idoso , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica , Neoplasias Ovarianas/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento , Células Tumorais CultivadasRESUMO
We conducted a Phase II clinical trial of the antiproliferative, antimetastatic, and antiangiogenic agent carboxyamido-triazole (CAI), using pharmacokinetic assessment to guide drug dosing. Fifteen patients who had stage D2 androgen-independent prostate cancer with soft tissue metastases were enrolled. Because CAI previously had been shown to decrease prostate-specific antigen secretion in vitro, this marker was not used to assess disease status. The dose of CAI used in this study was calculated so that plasma steady-state maximum concentrations between 2.0 and 5.0 microg/ml would be maintained. Following the initial dosage adjustment, 93% (14 of 15) of patients were within the predicted range. Fourteen of 15 patients were evaluable for response. All of the 14 evaluable patients demonstrated progressive disease at approximately 2 months. Twelve patients progressed by computed tomography and or bone scan at 2 months, whereas two patients demonstrated clinical progression at 1.5 and 2 months. One patient was removed from study at 6 weeks due to grade II peripheral neuropathy lasting >1 month. Although no clinical responses were noted, a 27.7% decrease in serum vascular endothelial growth factor concentration was observed. CAI does not possess clinical activity in patients with androgen-independent prostate cancer and soft tissue metastases. Pharmacokinetically guided dosing, although found to be feasible using a Bayesian approach, was not found to be of practical benefit. Although plasma CAI concentrations were maintained within the designated range, grade III toxicity requiring drug discontinuation was still observed.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Androgênios/fisiologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Triazóis/farmacocinética , Triazóis/uso terapêutico , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/metabolismo , Triazóis/efeitos adversosRESUMO
PURPOSE: Thalidomide is a potent teratogen that causes dysmelia in humans. Recently, in vitro data suggested that it inhibits angiogenesis. Prostate cancer is dependent on the recruitment of new blood vessels to grow and metastasize. Based on those data, we initiated a Phase II trial of thalidomide in patients with metastatic androgen-independent prostate cancer. EXPERIMENTAL DESIGN: This was an open-label, randomized Phase II study. Thalidomide was administered either at a dose of 200 mg/day (low-dose arm) or at an initial dose of 200 mg/day that escalated to 1200 mg/day (high-dose arm). RESULTS: A total of 63 patients were enrolled onto the study (50 patients on the low-dose arm and 13 patients on the high-dose arm). Serum prostate-specific antigen (PSA) decline of > or = 50% was noted in 18% of patients on the low-dose arm and in none of the patients on the high-dose arm. Four patients were maintained for > 150 days. The most prevalent complications were constipation, fatigue, neurocortical, and neurosensory. CONCLUSION: Thalidomide, an antiangiogenesis agent, has some activity in patients with metastatic prostate cancer who have failed multiple therapies. A total of 27% of all patients had a decline in PSA of > or = 40%, often associated with an improvement of clinical symptoms. Because our preclinical studies had shown that thalidomide increases PSA secretion, we believe that the magnitude of PSA decline seen in our trial justifies further study.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Talidomida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Androgênios/fisiologia , Relação Dose-Resposta a Droga , Fatores de Crescimento Endotelial/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Seguimentos , Humanos , Linfocinas/sangue , Linfocinas/efeitos dos fármacos , Linfotoxina-alfa/sangue , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/induzido quimicamente , Neovascularização Patológica/patologia , Neutropenia/induzido quimicamente , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/efeitos dos fármacos , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
OBJECTIVE: To evaluate the effects of treatment with alternating and simultaneous regimens of zidovudine and didanosine on neuropsychological function in patients with symptomatic HIV-1 disease, focusing on patients with possible HIV-1-associated central nervous system (CNS) compromise at entry. DESIGN: Randomized non-blinded clinical trial. SETTING: Government medical research center. PATIENTS: Thirty-eight patients with symptomatic HIV-1 disease, of whom 21 had evidence of CNS compromise at entry. RESULTS: After 12 weeks of therapy, overall significant improvements in memory (P < 0.01) and focused attention (P < 0.001) were seen on both regimens. These gains, however, were largely limited to those patients with HIV-1-associated CNS compromise at entry (P < 0.05). Improvements were also noted in receptive vocabulary, reading, perceptual discrimination and reasoning, divided attention, motor strength, and in mood and affect. Improvements in those latter functions were generally of limited magnitude and were of comparable size for both compromised and non-compromised patients. There was no overall difference between the two drug regimens in the effects on CNS parameters. CONCLUSIONS: Therapy-related improvements were noted particularly for patients with HIV-1-associated CNS compromise. Neuropsychological functions that have been implicated in AIDS dementia--memory and attention--showed the greatest gains. In contrast to the previously described superiority of the simultaneous regimen with regard to immunologic and virologic parameters, there was no difference between the regimens with regard to CNS measures. This supports the contention that the CNS constitutes a relative independent compartment in terms of HIV disease and treatment.