RESUMEN

BACKGROUND: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML. METHODS: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109 /L and ≥10 × 109 /L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1-year survival. The trial is registered at ClinicalTrials.gov (NCT01303796). RESULTS: Between October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109 /L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017). CONCLUSIONS: The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109 /L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

Asunto(s)

Arabinonucleósidos , Leucemia Mieloide Aguda , Anciano , Azacitidina , Citosina/análogos & derivados , Citosina/uso terapéutico , Decitabina , Humanos , Resultado del Tratamiento

RESUMEN

BACKGROUND: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. METHODS: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. RESULTS: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. INTERPRETATION: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. FUNDING: Cyclacel Limited.

Asunto(s)

Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/efectos adversos , Citosina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Administración Oral , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anemia/patología , Citosina/administración & dosificación , Citosina/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Masculino , Neutropenia/inducido químicamente , Neutropenia/patología , Neumonía/inducido químicamente , Neumonía/patología , Trombocitopenia/inducido químicamente , Trombocitopenia/patología

RESUMEN

AIM: Phase I study of seliciclib (CYC202, R-roscovitine), an inhibitor of cyclin-dependent kinases 2, 7 and 9, causing cell cycle changes and apoptosis in cancer cells. PATIENTS AND METHODS: This phase I trial aimed at defining the toxicity profile, the maximum tolerated dose (MTD), the recommended phase II dose (RD) and the main pharmacokinetic and pharmacodynamic parameters of oral seliciclib. Three schedules were evaluated: seliciclib given twice daily for 5 consecutive days every 3 weeks (schedule A), for 10 consecutive days followed by 2 weeks off (schedule B) and for 3d every 2 weeks (schedule C). RESULTS: Fifty-six patients received a total of 218 cycles of seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of seliciclib-induced cell death in the blood of patients treated with seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed. CONCLUSIONS: The MTD and RD for seliciclib are 1250 mg bid for 5d every 3 weeks and 1600 mg bid for 3d every 2 weeks, respectively.

Asunto(s)

Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Purinas/efectos adversos , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Enfermedades Metabólicas/inducido químicamente , Persona de Mediana Edad , Náusea/inducido químicamente , Purinas/administración & dosificación , Roscovitina , Vómitos/inducido químicamente

RESUMEN

PURPOSE: Sapacitabine is an oral deoxycytidine nucleoside analog with a unique mechanism of action that is different from cytarabine. PATIENTS AND METHODS: To define the dose-limiting toxicities (DLT) and maximum-tolerated dose (MTD) of sapacitabine given orally twice daily for 7 days every 3 to 4 weeks, or twice daily for 3 days for 2 weeks (days 1 through 3 and days 8 through 10) every 3 to 4 weeks, in refractory-relapse acute leukemia and myelodysplastic syndrome (MDS). A total of 47 patients were treated in the phase I study that used a classical 3 + 3 design. Sapacitabine was escalated from 75 to 375 mg twice daily for 7 days (n = 35) and from 375 to 475 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. RESULTS: The DLTs with both schedules were gastrointestinal. The MTDs were 375 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. The recommended phase II single-agent dose schedules were 325 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. Responses were observed in 13 patients (28%); four were complete responses, and nine were marrow complete responses. CONCLUSION: Sapacitabine is a new, safely administered, oral deoxycytidine analog that has encouraging activity in leukemia and MDS. Phase II studies are ongoing.

Asunto(s)

Arabinonucleósidos/administración & dosificación , Citosina/análogos & derivados , Leucemia/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Enfermedad Aguda , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Arabinonucleósidos/efectos adversos , Citosina/administración & dosificación , Citosina/efectos adversos , Esquema de Medicación , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Análisis de Supervivencia

RESUMEN

PURPOSE: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. EXPERIMENTAL DESIGN: Patients with treatment-naïve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. RESULTS: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T. CONCLUSIONS: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.

Asunto(s)

Antineoplásicos/uso terapéutico , Ciclo Celular/efectos de los fármacos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Purinas/uso terapéutico , Administración Oral , Adulto , Anciano , Apoptosis/efectos de los fármacos , Ciclina D1/análisis , ADN Viral/sangre , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/virología , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Purinas/efectos adversos , Purinas/sangre , Roscovitina

RESUMEN

A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade

Asunto(s)

Ácidos Hidroxámicos/administración & dosificación , Dosis Máxima Tolerada , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Inhibidores de Histona Desacetilasas , Humanos , Ácidos Hidroxámicos/toxicidad , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Terapia Recuperativa/métodos , Resultado del Tratamiento , Vorinostat

RESUMEN

This phase II trial was initiated to assess the efficacy and safety of oral vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Eligible patients must have recurrent and/or metastatic head and neck cancer unresponsive to or intolerant of conventional chemotherapy. Patients must have measurable disease, adequate hematologic, hepatic, and renal function, and be able to swallow capsules. Four or more weeks must have elapsed since prior chemotherapy, radiation therapy, major surgery or investigational anticancer therapy, and patients must have recovered from prior toxicities. Study endpoints included response rate, duration of stable disease and progression-free survival. Thirteen patients were enrolled (9 males); 1 withdrew consent prior to starting therapy. Twelve patients received oral vorinostat 400 mg once daily and were evaluable for response. The median age was 54 years (range 40-82). All patients had received prior chemotherapy (including 10 with platinum- or taxane-based combination therapy), and 9 had prior radiation therapy. No confirmed partial or complete responses were observed. One unconfirmed partial response was seen. Three patients had stable disease ranging from 9 to 26 weeks. Nine patients discontinued due to progressive disease, two withdrew consent, and one discontinued therapy for grade 3 anorexia. Grades 3-4 drug-related toxicities included thrombocytopenia (n=3), anorexia (n=2), and dehydration (n=2). Oral vorinostat 400 mg qd was generally well tolerated but did not demonstrate efficacy as defined by tumor response in this small group of heavily pre-treated patients.

Asunto(s)

Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Anorexia/inducido químicamente , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Cápsulas , Carcinoma de Células Escamosas/patología , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Índice de Severidad de la Enfermedad , Trombocitopenia/inducido químicamente , Factores de Tiempo , Resultado del Tratamiento , Vorinostat

RESUMEN

The activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) were evaluated in patients with refractory cutaneous T-cell lymphoma (CTCL). Group 1 received vorinostat 400 mg daily, group 2 received vorinostat 300 mg twice daily for 3 days with 4 days rest, and group 3 received vorinostat 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice daily. Treatment continued until disease progression or intolerable toxicity. The primary objective was to determine the complete and partial response (PR) rate. Time to response (TTR), time to progressive disease (TTP), response duration (DOR), pruritus relief, and safety were determined. Thirty-three patients who had received a median of 5 prior therapies were enrolled. Eight patients achieved a PR, including 7 with advanced disease and 4 with Sézary syndrome. The median TTR, DOR, and TTP for responders were 11.9, 15.1, and 30.2 weeks, respectively. Fourteen of 31 evaluable patients had pruritus relief. The most common drug-related AEs were fatigue, thrombocytopenia, diarrhea, and nausea. The most common grade 3 or 4 drug-related AEs were thrombocytopenia and dehydration. Vorinostat demonstrated activity in heavily pretreated patients with CTCL. The 400 mg daily regimen had the most favorable safety profile and is being further evaluated.

Asunto(s)

Antineoplásicos/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Deshidratación/inducido químicamente , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Linfocitos/patología , Linfoma Cutáneo de Células T/complicaciones , Masculino , Persona de Mediana Edad , Prurito/tratamiento farmacológico , Prurito/etiología , Inducción de Remisión , Terapia Recuperativa , Síndrome de Sézary/complicaciones , Síndrome de Sézary/tratamiento farmacológico , Piel/irrigación sanguínea , Piel/patología , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , Vorinostat

RESUMEN

BACKGROUND: Histone deacetylase inhibitors are a novel class of therapeutic agents that inhibit deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression. Phase I trials of intravenous and oral formulations of one such agent, vorinostat (suberoylanilide hydroxamic acid [SAHA]), have shown that it is safe and tolerable, that it inhibits histone deacetylation in peripheral blood mononuclear cells, and that it has a broad range of antitumor activity. PATIENTS AND METHODS: Thirteen patients with mesothelioma were included in a phase I trial of oral SAHA. All but one had previously been treated with chemotherapy. RESULTS: Four patients completed > or = 6 cycles of therapy; 2 patients demonstrated a partial response. The toxicities in this cohort of patients were similar to those observed in the entire phase I trial: primarily fatigue, dehydration, nausea, and vomiting. CONCLUSION: Given the dearth of treatment options for patients with advanced mesothelioma who have progressed after first-line chemotherapy, these results are encouraging. A placebo-controlled, randomized phase III study of oral SAHA is now open for patients with mesothelioma in whom treatment with pemetrexed has failed.

Asunto(s)

Inhibidores Enzimáticos/uso terapéutico , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/uso terapéutico , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Estudios de Cohortes , Esquema de Medicación , Femenino , Humanos , Masculino , Mesotelioma/diagnóstico por imagen , Mesotelioma/patología , Persona de Mediana Edad , Neoplasias Pleurales/diagnóstico por imagen , Neoplasias Pleurales/patología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Vorinostat

RESUMEN

PURPOSE: To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. PATIENTS AND METHODS: Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. RESULTS: Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. CONCLUSIONS: Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.

Asunto(s)

Inhibidores Enzimáticos/administración & dosificación , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Disponibilidad Biológica , Esquema de Medicación , Inhibidores Enzimáticos/farmacocinética , Femenino , Neoplasias Hematológicas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Vorinostat

RESUMEN

Histone deacetylase (HDAC) inhibitors represent a new class of targeted anticancer agents. A number of structural classes of HDAC inhibitors have been developed of which several are in clinical trials, including phenylbutyrate (PB) and related compounds; the hydroxamic acids, suberoylanilide hydroxamic acid (SAHA) and depsipeptide (FK-228); and the benzamides, MS-275 and C1-994. This review will focus on our studies with the hydroxamic acid HDAC inhibitors, of which SAHA is the lead agent. X-ray crystallographic studies with a HDAC homologue (HDLP) demonstrated that the hydroxamic acid group, most of the aliphatic chain and part of the phenyl amino group of SAHA inserts into the pocket-like catalytic site of the enzyme, at the base of which is a zinc molecule. SAHA inhibits the activity of class I and II HDACs and is selective in altering gene expression. SAHA is synergistic in its anticancer activity with radiation, kinase inhibitors, cytotoxic agents and differentiating agents. In phase I clinical trial with orally administered SAHA the agent caused accumulation of acetylated histones in peripheral mononuclear cells and tumour cells, has excellent bioavailability and has shown antitumour activity in patients with haematologic and solid tumours.

Asunto(s)

Inhibidores de Histona Desacetilasas , Neoplasias/tratamiento farmacológico , Histona Desacetilasas/clasificación , Humanos , Neoplasias Laríngeas/tratamiento farmacológico , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario

RESUMEN

PURPOSE: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer. EXPERIMENTAL DESIGN: SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues. RESULTS: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms. CONCLUSIONS: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.

Asunto(s)

Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/administración & dosificación , Acetilación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Área Bajo la Curva , Biopsia , Relación Dosis-Respuesta a Droga , Femenino , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacocinética , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Piel/patología , Factores de Tiempo , Resultado del Tratamiento , Vorinostat