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BACKGROUND: Cassava leaf samples degrade quickly during storage and transportation from distant areas. Proper sampling and efficient, low-cost storage methods are critical for obtaining sufficient quality DNA and RNA for plant virus epidemiology and improving disease control understanding. This is useful when samples are collected from remote areas far from a laboratory or in developing countries where money and materials for virus diagnostics are scarce. RESULTS: The effect of sample storage duration on nucleic acid (N.A.) quality on virus detection was investigated in this study. A simple, rapid, and cost-effective CTAB-based approach (M3) for single N.A. extraction was optimized and tested alongside two existing CTAB-based methods (M1 and M2) for N.A. extraction from fresh and herbarium cassava leaves stored for; 1, 8, 26, and 56 months. The amount and quality of DNA and RNA were determined using Nanodrop 2000 c U.V.-vis Spectrophotometer and agarose gel electrophoreses. The sample degradation rate was estimated using a simple mathematical model in Matlab computational software. The results show no significant difference in mean DNA concentration between M1 and M2 but a significant difference between M3 and the other two methods at p < 0.005. The mean DNA concentration extracted using M3 was higher for 1 and 8 months of leave storage. M3 and M2 produced high concentrations at 26 and 56 months of leave storage. Using a developed scale for quality score, M3 and M2 produced high-quality DNA from fresh samples. All methods produced poor-quality DNA and RNA at 8 and 26 months of leave storage and no visual bands at the age of 56 months. Statistically, there was a significant difference in the mean DNA quality between M1 and M2, but there was no significant difference between M3 and the other two methods at p < 0.005. However, Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV) were readily detected by RT-PCR from RNA isolated using M3. The quality of DNA declined per storage time at 0.0493 and 0.0521/month, while RNA was 0.0678 and 0.0744/month. Compared to the existing two methods, modified CTAB extracted enough high-quality N.A. in one-third the time of the existing two methods. CONCLUSION: Our method provides cost-effective, quick, and simple processing of fresh and dry samples, which will quicken and guide the decision on when and what type of sample to process for plant disease management and surveillance actions.
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Aminopiridinas , Pirazóis , Aminopiridinas/efeitos adversos , Humanos , Lactamas , Lactamas MacrocíclicasRESUMO
Lorlatinib is a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinases and is approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). In the phase I/II study (NCT01970865), potential exposure-response (E-R) relationships between lorlatinib and selected safety and efficacy end points were evaluated in patients with NSCLC. E-R relationships were assessed for safety end points with incidence > 10% in all treated patients (n = 328). In total, 4 safety end points were assessed: hypercholesterolemia grade ≥ 3, hypertriglyceridemia grade ≥ 3, weight gain grade ≥ 2, and treatment-emergent adverse events (TEAEs) grade ≥ 3. Using logistic regression, significant relationships were identified between lorlatinib plasma exposure and risk of hypercholesterolemia grade ≥ 3 (odds ratio (OR) 5.256) and risk of TEAE grade ≥ 3 (OR 3.214). The covariates baseline cholesterol and time on study prior to the event (TE) were associated with the probability of hypercholesterolemia grade ≥ 3. Baseline cholesterol and TE were found to have a statistically significant correlation with TEAE grade ≥ 3. Exposure-efficacy relationships were assessed for objective response rate (ORR; n = 197) and intracranial objective response rate (IC-ORR; n = 132). Lorlatinib plasma exposure was not identified as a statistically significant factor related to either efficacy end point. The only significant E-R relationships identified for efficacy were between baseline alkaline phosphatase and baseline amylase with IC-ORR (ORs 0.363 and 1.015, respectively). These findings support the lorlatinib indicated dose and dose modification guidelines regarding the management of lorlatinib-related AEs.
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Aminopiridinas/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipercolesterolemia/induzido quimicamente , Lactamas/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Pirazóis/efeitos adversos , Adulto , Idoso , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Feminino , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/metabolismo , Lactamas/farmacocinética , Lactamas/uso terapêutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Medição de Risco/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Bendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment. METHODS: This was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120âmg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR. RESULTS: A total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%-81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2âmonths by IRC and 13.4âmonths by investigator assessment; the median PFS was 18.6âmonths and 15.3âmonths, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities. CONCLUSION: Bendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, No. NCT01596621; https://clinicaltrials.gov/ct2/show/NCT01596621.
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Linfoma não Hodgkin , Recidiva Local de Neoplasia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina/uso terapêutico , China , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Rituximab/uso terapêuticoRESUMO
In the original article, the reference 4 has been published and cited incorrectly.
RESUMO
INTRODUCTION: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. METHODS: This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib. RESULTS: When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2-4 in 11 participants) within 1-3 days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15 days). No elevations in bilirubin were observed. CONCLUSIONS: The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02804399.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas Macrocíclicas/farmacocinética , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Rifampina/farmacocinética , Rifampina/uso terapêutico , Adulto , Aminopiridinas , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Lactamas , Masculino , Pessoa de Meia-Idade , Pirazóis , Adulto JovemRESUMO
BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. METHODS: In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. FUNDING: Pfizer.
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Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Rearranjo Gênico , Humanos , Lactamas , Lactamas Macrocíclicas/efeitos adversos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis , Fatores de Tempo , Carga TumoralRESUMO
BACKGROUND: Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC. METHODS: In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. FINDINGS: Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79). INTERPRETATION: In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). FUNDING: Pfizer.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Rearranjo Gênico/efeitos dos fármacos , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Adulto , Idoso , Aminopiridinas , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Internacionalidade , Lactamas , Lactamas Macrocíclicas/efeitos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Dose Máxima Tolerável , Pessoa de Meia-Idade , Seleção de Pacientes , Prognóstico , Estudos Prospectivos , Proteínas Tirosina Quinases/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Pirazóis , Receptores Proteína Tirosina Quinases/genética , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Bendamustine hydrochloride (bendamustine) was approved for first-line treatment of patients with chronic lymphocytic leukemia (CLL) and relapsed indolent B-cell non-Hodgkin's lymphoma (NHL). Pharmacovigilance data have been collected since bendamustine's approval to enhance understanding of its long-term safety profile. Here we provide an overview of the pharmacovigilance data for bendamustine that have led to label updates related to safety and administration since its approval. RESEARCH DESIGN AND METHODS: Adverse events (AEs) captured from 12 quarterly postmarketing periodic adverse drug experience reports spanning 2008-2015 were included and summarized. AEs were classified as serious or nonserious and expected or unexpected. RESULTS: Adverse events that resulted in label updates included Stevens-Johnson syndrome, toxic epidermal necrolysis, extravasation, secondary neoplasm, and drug reactions with eosinophilia and systemic symptoms. Preventive measures for tumor lysis syndrome were revised. Although this review may be limited by voluntary reporting, the adverse events reported for bendamustine in a large, heterogeneous population with a long follow-up relative to recently approved treatments provide a much broader understanding of its safety profile. CONCLUSIONS: Based on these observational data, bendamustine appears to have a favorable risk-benefit profile and remains a useful option when considering a management strategy in patients with CLL and NHL.
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Antineoplásicos Alquilantes/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Sistemas de Notificação de Reações Adversas a Medicamentos , Antineoplásicos Alquilantes/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Humanos , Farmacovigilância , Vigilância de Produtos ComercializadosRESUMO
Ambulation is defined by duration, distance traversed, number and size of directional changes, and the interval separating successive movement episodes; more complex measures of ambulation can be created by aggregating these features. This review article of published findings defines random changes in direction during movement as "movement path tortuosity" and relates tortuosity to the understanding of cognitive impairments of persons of all ages. Path tortuosity is quantified by subjecting tracking data to fractal analysis, specifically Fractal Dimension (Fractal D), which ranges from a value of 1 when the movement path is perfectly straight to a value of 2 when the movement path is random, resembling the "drunkard's walk." The review elucidates the mathematical assumptions underlying Fractal D, its use in the analysis of movements of free ranging animals, and its application to the study of cognitive impairment and the prediction of falls in older adults. We conclude Fractal D offers a reliable, valid, sensitive, and easily interpreted real-time longitudinal measure of unrestricted movement path tortuosity unaffected by mobility aid use.
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Envelhecimento/fisiologia , Transtornos Cognitivos/fisiopatologia , Biologia Computacional/métodos , Fractais , Caminhada/fisiologia , Animais , Encefalopatias/fisiopatologia , Marcha , Humanos , Comportamento Errante/fisiologiaRESUMO
INTRODUCTION: This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non-small cell lung cancer. METHODS: Patients with progression after at least one line of chemotherapy or targeted therapy received dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity; the expansion cohorts received the maximum tolerated dose of the combination. The primary objective was to define the recommended phase II dose; secondary objectives included assessment of safety and activity of the combination in epidermal growth factor receptor inhibitor-resistant patients and correlation with tumor biomarkers. RESULTS: Seventy patients were treated in the dose-escalation (n = 33) and expansion phases (n = 37), with the maximum tolerated dose defined as dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%), rash (7%), and fatigue (6%). There were 16 deaths; none were considered treatment related. One patient (1%) had a partial response; 46% had stable disease. Most of the tumor samples analyzed had activating epidermal growth factor receptor gene (EGFR) mutations (18 of 20 [90%]); 50% (10 of 20) had a concurrent resistance mutation. Only one sample showed MMNG HOS Transforming gene (MET) amplification (the patient had progressive disease), whereas 59% (13 of 22) and 47% (14 of 30) had high levels of expression of epidermal growth factor receptor and mesenchymal-epithelial transition factor on the basis of H-scores, respectively. There was no apparent association between biomarker expression and antitumor activity. CONCLUSION: The combination of dacomitinib and crizotinib showed limited antitumor activity in patients with advanced non-small cell lung cancer and was associated with substantial toxicity.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Crizotinibe , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Proto-Oncogene Mas , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Quinazolinonas/administração & dosagem , Taxa de SobrevidaRESUMO
In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Aminopiridinas , Quinase do Linfoma Anaplásico , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Crizotinibe , Feminino , Humanos , Lactamas , Falência Hepática/etiologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Estrutura Molecular , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sulfonas/uso terapêuticoRESUMO
INTRODUCTION: Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities. METHODS: Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response. RESULTS: Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2). CONCLUSIONS: Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.
Assuntos
Adenocarcinoma/tratamento farmacológico , Aminopterina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Suplementos Nutricionais , Neoplasias Pulmonares/tratamento farmacológico , Complexo Vitamínico B/administração & dosagem , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Aminopterina/farmacocinética , Aminopterina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Ácido Fólico/administração & dosagem , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Distribuição Tecidual , Vitamina B 12/administração & dosagemRESUMO
PURPOSE: We use changes in tumor measurements to assess response and progression, both in routine care and as the primary objective of clinical trials. However, the variability of computed tomography (CT) -based tumor measurement has not been comprehensively evaluated. In this study, we assess the variability of lung tumor measurement using repeat CT scans performed within 15 minutes of each other and discuss the implications of this variability in a clinical context. PATIENTS AND METHODS: Patients with non-small-cell lung cancer and a target lung lesion ≥ 1 cm consented to undergo two CT scans within a period of minutes. Three experienced radiologists measured the diameter of the target lesion on the two scans in a side-by-side fashion, and differences were compared. RESULTS: Fifty-seven percent of changes exceeded 1 mm in magnitude, and 33% of changes exceeded 2 mm. Median increase and decrease in tumor measurements were +4.3% and -4.2%, respectively, and ranged from 23% shrinkage to 31% growth. Measurement changes were within ± 10% for 84% of measurements, whereas 3% met criteria for progression according to Response Evaluation Criteria in Solid Tumors (RECIST; ≥ 20% increase). Smaller lesions had greater variability of percent measurement change (P = .005). CONCLUSION: Apparent changes in tumor diameter exceeding 1 to 2 mm are common on immediate reimaging. Increases and decreases less than 10% can be a result of the inherent variability of reimaging. Caution should be exercised in interpreting the significance of small changes in lesion size in the care of individual patients and in the interpretation of clinical trial results.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy. METHODS: This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14mg/m(2) on days 1 and 3 with IV topotecan at 1.25mg/m(2) on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate. RESULTS: Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%). CONCLUSION: Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirróis/administração & dosagem , Idoso , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/fisiopatologia , Progressão da Doença , Feminino , Humanos , Indóis , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Pirróis/efeitos adversos , Pirróis/farmacologia , Recidiva , Trombocitopenia/etiologia , Topotecan/administração & dosagem , Topotecan/efeitos adversosRESUMO
PURPOSE: Paclitaxel is an effective therapy for patients with solid tumors. While the albumin-bound formulation eliminates the hypersensitivity reaction caused by the Cremaphor solvent, significant peripheral neuropathy persists when given over the standard 30-min infusion time. We sought to determine if the incidence and severity of peripheral neuropathy could be reduced when the infusion time is lengthened to 2-h. METHODS: This was an open-label, single-arm, phase 2 study of albumin-bound paclitaxel given over 2 h. Twenty-five patients with advanced non-small-cell lung cancer were enrolled to determine whether the longer infusion reduced the severity of neuropathy compared to data from an earlier cohort of 40 similar patients treated over 30 min Patients received 125 mg/m(2) of albumin-bound paclitaxel IV over 2 h without premedication on days 1, 8, and 15 of a 28-day cycle. Radiologic assessment was performed every 8 weeks. RESULTS: There was a significant 0.45 grade decrease in average peripheral neuropathy experienced by patients in the 2-h group versus the 30-min group (90% CI, 0.03-0.87). There was, in addition, a significant decrease in grade ≥2 peripheral neuropathy in patients treated over 2 h versus 30 min (28% vs. 55%, 2-sided P = 0.04). A decrease in grade ≥2 neutropenia (20% vs. 48%, 2-sided P = 0.07) was also observed. The median survival, 11 months, was the same for both groups. CONCLUSION: Increasing the infusion time of albumin-bound paclitaxel from 30 min to 2 h resulted in a significant reduction in both average and grade ≥2 peripheral neuropathy without affecting survival.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Paclitaxel Ligado a Albumina , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Albuminas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Análise de SobrevidaRESUMO
PURPOSE: To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies. PATIENTS AND METHODS: Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m(2) by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m(2) was given concurrently as an IV infusion on days 1-5 of each cycle. RESULTS: Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m(2) on day 1, 14 mg/m(2) on days 1 and 3, and 20 mg/m(2) on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m(2); no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m(2) on day 1, the level was escalated to 14 mg/m(2) on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m(2) on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks. CONCLUSION: Obatoclax mesylate administered at 14 mg/m(2) IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m(2) IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Pirróis/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Indóis , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Mesilatos/administração & dosagem , Pessoa de Meia-Idade , Seleção de Pacientes , Pirróis/efeitos adversos , Recidiva , Topotecan/administração & dosagemRESUMO
PURPOSE: To evaluate the variability of tumor unidimensional, bidimensional, and volumetric measurements on same-day repeat computed tomographic (CT) scans in patients with non-small cell lung cancer. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board, with informed patient consent. Thirty-two patients with non-small cell lung cancer, each of whom underwent two CT scans of the chest within 15 minutes by using the same imaging protocol, were included in this study. Three radiologists independently measured the two greatest diameters of each lesion on both scans and, during another session, measured the same tumors on the first scan. In a separate analysis, computer software was applied to assist in the calculation of the two greatest diameters and the volume of each lesion on both scans. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess the agreements between the measurements of the two repeat scans (reproducibility) and between the two repeat readings of the same scan (repeatability). RESULTS: The reproducibility and repeatability of the three radiologists' measurements were high (all CCCs, >or=0.96). The reproducibility of the computer-aided measurements was even higher (all CCCs, 1.00). The 95% limits of agreements for the computer-aided unidimensional, bidimensional, and volumetric measurements on two repeat scans were (-7.3%, 6.2%), (-17.6%, 19.8%), and (-12.1%, 13.4%), respectively. CONCLUSION: Chest CT scans are well reproducible. Changes in unidimensional lesion size of 8% or greater exceed the measurement variability of the computer method and can be considered significant when estimating the outcome of therapy in a patient.