RESUMO
INTRODUCTION: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. METHODS: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. RESULTS: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. CONCLUSIONS: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.
Assuntos
Códon sem Sentido/genética , Distrofina/genética , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Oxidiazóis/uso terapêutico , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Cooperação Internacional , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Fatores de Tempo , CaminhadaRESUMO
RATIONALE: Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. OBJECTIVES: To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. METHODS: Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. MEASUREMENTS AND MAIN RESULTS: The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. CONCLUSIONS: In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.
Assuntos
Códon sem Sentido/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/biossíntese , Fibrose Cística/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Oxidiazóis/uso terapêutico , Adolescente , Criança , Códon sem Sentido/genética , Códon sem Sentido/fisiologia , Estudos Cross-Over , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Mucosa Nasal/metabolismo , Mucosa Nasal/fisiopatologia , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacologiaRESUMO
In this study we used the 6-minute walk distance (6MWD) to characterize ambulation over time in Duchenne/Becker muscular dystrophy (DBMD). The 6MWD was assessed in 18 boys with DBMD and 22 healthy boys, ages 4-12 years, over mean [range] intervals of 58 [39-87] and 69 [52-113] weeks, respectively. Height and weight increased similarly in both groups. At 52 weeks, 6MWD decreased in 12 of 18 (67%) DBMD subjects (overall mean [range]: 357 [125-481] to 300 [0-510] meters; Δ -57 meters, -15.9%), but increased in 14 of 22 (64%) healthy subjects (overall mean [range]: 623 [479-754] to 636 [547-717] meters; Δ +13 meters, +2.1%). Two DBMD subjects lost ambulation. Changes in 6MWD depended on stride length and age; improvements usually occurred by 7-8 years of age; older DBMD subjects worsened, whereas older healthy subjects were stable. The 6MWD changes at 1 year confirm the validity of this endpoint and emphasize that preserving ambulation must remain a major goal of DBMD therapy.
Assuntos
Marcha/fisiologia , Distrofia Muscular de Duchenne/fisiopatologia , Caminhada/fisiologia , Estatura , Peso Corporal , Criança , Pré-Escolar , Progressão da Doença , Seguimentos , Humanos , MasculinoRESUMO
Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6-minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, approximately 1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean +/- SD [range] 6-minute walk distance (6MWD) was lower in boys with DMD than in controls (366 +/- 83 [125-481] m vs. 621 +/- 68 [479-754] m; P < 0.0001; unpaired t-test). Test-retest correlation for boys with DMD was high (r = 0.91). Stride length (R(2) = 0.89; P < 0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease-related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials.
Assuntos
Teste de Esforço/métodos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/fisiopatologia , Caminhada/fisiologia , Criança , Pré-Escolar , Teste de Esforço/normas , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
Objective: The developmental maturation of forward and backward digit spans-indices of working memory-in boys with nonsense (nm) Duchenne muscular dystrophy (DMD) (nmDMD) was assessed using prospective, longitudinal data. Methods: Fifty-five boys of the 57 subjects with genetically confirmed nmDMD-who were from the placebo arm of a 48-week-long phase 2b clinical trial-were evaluated. Forward and backward digit spans were obtained every 12 weeks for a total of five assessments in all study subjects. Changes in forward and backward digit spans were evaluated based on age, corticosteroid treatment, and DMD mutation location. Results: Boys with nmDMD had lower mean scores on normalized forward digit span. Normalized forward digit spans were comparable between subjects stratified by age and between corticosteroid-naïve and corticosteroid-treated subjects. When stratified by DMD mutation location, normalized forward digit spans were lower in nmDMD subjects with mutations downstream of DMD exon 30, exon 45, and exon 63, both at baseline evaluation and at follow-up evaluation at 48 weeks. On average, normalized backward digit span scores were stable over 48 weeks in these subjects. Developmental growth modeling showed that subjects with nmDMD mutations upstream of DMD exon 30, upstream of DMD exon 45, and upstream of DMD exon 63 appeared to make better gains in working memory than subjects with mutations downstream of DMD exon 30, downstream of DMD exon 45, and downstream of DMD exon 63. Conclusion: Performance in working memory shows deficits in nmDMD and differed based on nmDMD location. Maturation in cognition was seen over a 48-week period. The developmental trajectory of working memory in this cohort was influenced by DMD mutation location.
RESUMO
BACKGROUND: In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. METHODS: This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. FINDINGS: Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p<0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0.0001) and in eight of the 21 patients in the second cycle (p<0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. INTERPRETATION: In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.
Assuntos
Códon de Terminação/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Oxidiazóis/uso terapêutico , Adolescente , Adulto , Cloretos/metabolismo , Códon sem Sentido/efeitos dos fármacos , Códon sem Sentido/genética , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxidiazóis/efeitos adversos , Oxidiazóis/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the relationship between deficit in digit span and genotype in nonsense mutation (nm) Duchenne muscular dystrophy (DMD) (nmDMD). METHODS: We investigated the relationship between normalized digit-span forward (d-sf) and digit-span backward (d-sb) scores to the location of nmDMD mutations in 169 participants ≥5 to ≤20 years who participated in a phase 2b clinical trial. Because alternative promoters are found upstream of DMD exons 30, 45, and 63, we correlated d-sf and d-sb to the specific nmDMD mutation location. RESULTS: Participants with nm downstream of exon 30, downstream of exon 45, and downstream of exon 63 had significantly lower normalized d-sf scores (p < 0.0001). Participants with nm downstream of exon 45 in addition had significantly lower normalized d-sb score (p < 0.04). There was no significant difference in the normalized d-sb score in participants with mutations upstream or downstream of DMD exon 30 or upstream or downstream of DMD exon 63. CONCLUSION: Our data provide evidence that specific cognitive deficits correlate to genotype in individuals with nmDMD, highlighting the critical role of brain-specific dystrophin isoforms in the neurobiological manifestations of this disease. CLINICALTRIALSGOV IDENTIFIER: NCT02090959.
Assuntos
Códon sem Sentido , Memória de Curto Prazo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/psicologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Humanos , Masculino , Testes Neuropsicológicos , Adulto JovemRESUMO
Nonsense (premature stop codon) mutations are causative in 5% to 15% of patients with monogenetic inherited disorders. PTC124, a 284-Dalton 1,2,4-oxadiazole, promotes ribosomal readthrough of premature stop codons in mRNA and offers therapeutic potential for multiple genetic diseases. The authors conducted 2 phase I studies of PTC124 in 62 healthy adult volunteers. The initial, single-dose study evaluated doses of 3 to 200 mg/kg and assessed fed-fasting status on pharmacokinetics following a dose of 50 mg/kg. The subsequent multiple-dose study evaluated doses from 10 to 50 mg/kg/dose twice per day (bid) for up to 14 days. PTC124 administered orally as a liquid suspension was palatable and well tolerated through single doses of 100 mg/kg. At 150 and 200 mg/kg, PTC124 induced mild headache, dizziness, and gastrointestinal events. With repeated doses through 50 mg/kg/dose bid, reversible transaminase elevations <2 times the upper limit of normal were sometimes observed. Immunoblot analyses of peripheral blood mononuclear cell extracts revealed no protein elongation due to nonspecific ribosomal readthrough of normal stop codons. PTC124 plasma concentrations exceeding the 2- to 10-microg/mL values associated with activity in preclinical genetic disease models were safely achieved. No sex-related differences in pharmacokinetics were seen. No drug accumulation with repeated dosing was apparent. Diurnal variation was observed, with greater PTC124 exposures after evening doses. PTC124 excretion in the urine was <2%. PTC124 pharmacokinetics were described by a 1-compartment model. Collectively, the data support initiation of phase II studies of PTC124 in patients with nonsense mutation-mediated cystic fibrosis and Duchenne muscular dystrophy.
Assuntos
Códon sem Sentido/antagonistas & inibidores , Oxidiazóis/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Ritmo Circadiano , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Interações Alimento-Droga , Meia-Vida , Humanos , Immunoblotting , Masculino , Oxidiazóis/administração & dosagem , Oxidiazóis/efeitos adversosRESUMO
PURPOSE: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. EXPERIMENTAL DESIGN: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 x institutional upper limit of normal (IULN) and ALT/AST Assuntos
Camptotecina/análogos & derivados
, Hepatopatias/patologia
, Neoplasias/metabolismo
, Adulto
, Idoso
, Antineoplásicos Fitogênicos/administração & dosagem
, Antineoplásicos Fitogênicos/sangue
, Antineoplásicos Fitogênicos/farmacocinética
, Antineoplásicos Fitogênicos/toxicidade
, Área Sob a Curva
, Bilirrubina/sangue
, Camptotecina/administração & dosagem
, Camptotecina/sangue
, Camptotecina/farmacocinética
, Camptotecina/toxicidade
, Diarreia/induzido quimicamente
, Feminino
, Humanos
, Infusões Intravenosas
, Irinotecano
, Testes de Função Hepática
, Masculino
, Taxa de Depuração Metabólica
, Pessoa de Meia-Idade
, Neoplasias/sangue
, Neoplasias/patologia
, Neutropenia/induzido quimicamente
, Seleção de Pacientes
RESUMO
PURPOSE: This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. RESULTS: Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). CONCLUSION: Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Camptotecina/análogos & derivados , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Desoxicitidina/administração & dosagem , Progressão da Doença , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Radiografia , Segurança , Taxa de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
This phase II study was designed to evaluate the safety, tolerability, and efficacy of irinotecan (CPT-11) in the treatment of adults with malignant glioma. Patients with progressive or recurrent malignant gliomas were enrolled. CPT-11 was administered as a 90-minute intravenous infusion at a dose of 300 mg/m(2) once a week every 3 weeks. After 2 treatments, doses were increased to 350 mg/m(2) in those patients without grade III/IV toxicities. Dose modifications were made for toxicities. All 14 patients who enrolled (11 males and 3 females) were treated with CPT-11 and were assessable for survival, response, and toxicity. The majority of patients (86%) had prior surgery. Two patients had a confirmed partial response and 2 patients (14%) had stable disease. Median survival was 24 weeks. Median time to tumor progression was 6 weeks. The primary hematologic toxicity was grade III/IV neutropenia, which was observed in 14% of patients. Infrequent grade III/IV nonhematologic toxicity was observed, possibly because of the concomitant use of anticonvulsants, which may have altered pharmacokinetics. These results suggest that CPT-11 has activity against recurrent malignant glioma using a dosing regimen of 300 mg/m(2) every 3 weeks showing limited toxicity. The concurrent use of anticonvulsant medications may have played a role in altering pharmacokinetics and thus the maximum tolerated dose in this patient population.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores da Topoisomerase I , Adulto , Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
BACKGROUND: Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis. METHODS: This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205. FINDINGS: Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% [95% CI -0.8 to 6.3]; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 [95% CI 0.57-1.05]; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% [-4.0 to 2.1] vs -6.4% [-9.8 to -3.7]; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events [0.9-1.9] vs 2.18 events [1.6-2.7]; rate ratio 0.60 [0.42-0.86]; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group. INTERPRETATION: Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin. FUNDING: PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Oxidiazóis/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Adolescente , Adulto , Antibacterianos/administração & dosagem , Criança , Cloretos/análise , Códon sem Sentido , Fibrose Cística/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Oxidiazóis/efeitos adversos , Suor/química , Tobramicina/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Although cough is a commonly reported symptom, objective quantitation of cough during normal activity has not been performed in patients with CF. METHODS: An ambulatory device was used to characterize cough over 24 hours. Pulmonary function and subject-reported coughing were also assessed. RESULTS: Patients included 19 clinically stable adults with CF (males:females=10:9; median age [range]=26 [19-57] years; median %-predicted FEV(1) [range]=65 [44-106]%). Median [range] cough rate was 27 [13-66] coughs/hour, with values while awake of 41 [20-102] and while asleep of 2 [0.1-7] (p<0.0001, Wilcoxon signed-rank test). Subjective reporting was consistent with objective data for wake-sleep differences, but correlated poorly with objective waking cough rate. CONCLUSIONS: Outpatient cough quantitation in patients with CF is feasible, indicates frequent coughing even during clinical stability, and may be useful in therapeutic trials in CF.
Assuntos
Tosse/etiologia , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Monitorização Ambulatorial , Sono , Vigília , Adulto , Tosse/fisiopatologia , Fibrose Cística/diagnóstico , Fibrose Cística/psicologia , Estudos de Viabilidade , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial/efeitos adversos , Cooperação do Paciente , Fatores de Tempo , Adulto JovemRESUMO
PURPOSE: The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. PATIENTS AND METHODS: Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. RESULTS: In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. CONCLUSION: PFS is an acceptable surrogate for OS in advanced colorectal cancer.
Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/tratamento farmacológico , Progressão da Doença , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagemRESUMO
Two studies were performed to evaluate the safety, tolerability, and efficacy of irinotecan (CPT-11) in the treatment of adults with malignant glioma. Patients with progressive or recurrent malignant gliomas were enrolled. In the first study, CPT-11 was administered once every 3 weeks as a 90-minute intravenous infusion at a dose of 300 mg/m(2). After 2 treatments, doses were increased to 350 mg/m(2) in those patients without Grade 3/4 toxicities. Dose modifications were made for toxicities. All 14 patients who enrolled (11 males and 3 females) were treated with CPT-11 and were assessable for survival, response, and toxicity. The majority of patients (86%) had prior surgery. Two patients had a confirmed partial response (PR), and 2 patients (14%) had stable disease (SD). Median survival was 24 weeks; median time to tumor progression (TTP) was 6 weeks. The primary hematologic toxicity was Grade 3/4 neutropenia, which was observed in 14% of patients. Infrequent Grade 3/4 nonhematologic toxicity was observed, possibly due to the concomitant use of anticonvulsants that might have altered pharmacokinetics. The second study evaluated the potential underdosing observed in patients who did or did not receive enzyme-inducing antiepileptic drugs (EIAED) by implementing an intrapatient dose escalation design. In this open-label study, treatment of patients with recurrent malignant glioma (rMG) was started at 300-400 mg/m(2) of CPT-11 every 3 weeks and, depending on individual safety and efficacy evaluation, escalated by steps of 100 mg/m(2) in subsequent courses. Thirty-five patients (median age, 43 years; gender, 11F and 24M; histology, 26 glioblastoma multiforme and 9 anaplastic glioma) have completed at least two cycles of chemotherapy and are evaluable for toxicity and response. Dose-limiting toxicity (DLT) was reached in 12 patients at doses ranging from 400-1700 mg/m(2). Preliminary efficacy data show that 3 patients exhibited PR and 15 patients exhibited SD. Median TTP was 2.7 months, and median survival was 8.5 months. Patients who did not receive anticonvulsants achieved higher peak concentrations, relative to dose, of the active metabolite SN-38 than did patients in the EIAED group. This study confirmed the activity of CPT-11 in malignant glioma and indicated that the maximum tolerated dose (MTD) for patients with rMG was considerably higher than expected but still possessed significant variability. A higher level of efficacy for CPT-11 may be observed if an MTD can efficiently be established for each patient.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Glioma/tratamento farmacológico , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Antineoplásicos Fitogênicos/toxicidade , Camptotecina/toxicidade , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Irinotecano , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Segurança , Resultado do TratamentoRESUMO
BACKGROUND: This Phase II multicenter, open-label, single-arm study evaluated the efficacy and safety of a three-drug combination of irinotecan (CPT-11), paclitaxel, and carboplatin in advanced nonsmall cell lung carcinoma (NSCLC). METHODS: Patients received repeated 21-day cycles at starting doses of paclitaxel 175 mg/m(2) administered over 3 hours, followed by carboplatin AUC of 5 over 30 minutes and CPT-11 at a starting dose level of 100 mg/m(2) over 90 minutes, all given on the first day of each cycle. Patients were evaluated for objective tumor response, time to tumor progression (TTP), survival, and safety. RESULTS: Forty patients were enrolled. Baseline patient characteristics included: median age 58 years (range, 32-79); 23 males and 17 females; performance status of 0 (21 patients), 1 (18 patients), or 2 (1 patient); and Stage IIIB (10 patients) and Stage IV (30 patients) disease. A median of six cycles (range, one to eight) were administered. Grade 3-4 toxicities observed in >/= 10% of the patients included neutropenia (78%), asthenia (20%), diarrhea (20%), nausea (18%), vomiting (13%), anemia (10%), and dyspnea (10%). Febrile neutropenia occurred in eight patients (20%), with one death due to neutropenic sepsis. Twelve of 38 evaluable patients had confirmed tumor responses (32%), while 21 (55%) had stable disease (including 12 patients [32%] with minor responses). Only 13% had disease progression at their initial tumor assessment. The median TTP and survival were 5.3 months (range, 0.03-6.2 months) and 12.5 months (range 0.3-28.6+ months), respectively. The one and two year survival probabilities were 0.50 (95% confidence interval [CI], 0.28-0.73) and 0.21 (95% CI, 0.0-0.67), respectively. CONCLUSIONS: The combination of CPT-11, paclitaxel, and carboplatin can be safely administered and is active in the treatment of advanced NSCLC. Based on the favorable survival outcome, this regimen is undergoing evaluation in prospective randomized trials.