RESUMO
BACKGROUND: Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints. METHODS: Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2. RESULTS: Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles. CONCLUSIONS: The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.
Assuntos
Irinotecano , Neoplasias , Sorafenibe , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Dose Máxima Tolerável , Recidiva Local de Neoplasia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêuticoRESUMO
BACKGROUND: Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive-dosing formula performance. PROCEDURE: Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half-life were available were used to compare formulas. RESULTS: Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2 . The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL ⢠min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96-1 737) mg/m2 . CONCLUSIONS: Wide variation in GFR obtained with nuclear-medicine-based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body-surface-area-based dosing.
Assuntos
Antineoplásicos/farmacocinética , Carboplatina/farmacocinética , Rim/fisiopatologia , Neoplasias/tratamento farmacológico , Medicina Nuclear , Cintilografia/métodos , Algoritmos , Antineoplásicos/administração & dosagem , Área Sob a Curva , Carboplatina/administração & dosagem , Criança , Seguimentos , Taxa de Filtração Glomerular , Humanos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , PrognósticoRESUMO
Children with high-risk neuroblastoma are currently treated with a chimeric monoclonal antibody against GD2 ganglioside (chimeric 14.18). The treatment improves survival but causes transient neuropathic pain-like syndrome. We retrospectively studied 16 children with neuroblastoma receiving GD2 therapy. To manage pain, all patients received morphine via nurse-controlled analgesia or patient-controlled analgesia. Mean daily pain scores ranged from 0 to 5 and all children had a 0 pain score upon discharge. No major side effects were noted, suggesting morphine via nurse-controlled analgesia/patient-controlled analgesia is effective in controlling transient neuropathic pain in children receiving GD2 antibody therapy.
Assuntos
Analgésicos Opioides/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Morfina/administração & dosagem , Neuralgia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Analgesia Controlada pelo Paciente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neuralgia/induzido quimicamente , Manejo da Dor/métodosRESUMO
BACKGROUND: Pediatric participants on phase 1 or phase 2 clinical trials for incurable cancer are at risk of experiencing toxicities (adverse events [AEs]) related to trial participation. Multiple AEs are subjective; thus, the real impact of trial treatment cannot be known unless patient subjective reports are solicited. METHODS: The authors assessed the feasibility and acceptability of soliciting symptom, function, and quality of life (QOL) reports from participants aged 8 to 18 years who were enrolled on phase 1/2 clinical trials at 4 cancer centers during the first course of chemotherapy. The authors also assessed the reliability and validity of 6 self-report Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric measures and 4 open-ended interview questions at 2 time points (at the time of trial enrollment [T1] and 3 to 4 weeks later [T2]). RESULTS: The enrollment rate of 75.9% (20 participants) exceeded the feasibility criterion, and missingness of measures by person, measure, and items at T1 and T2 were lower than the acceptability criteria. New QOL themes were limited to the impact of treatment on families and being away from home, family, and friends for treatment. All but one measure at T1 met the reliability criterion and all measures did so at T2. Validity support was limited however because as theorized, mobility decreased and fatigue increased as AEs increased. CONCLUSIONS: Soliciting and documenting symptom, function, and QOL reports from patients aged 8 to 18 years who are enrolled on a phase 1/2 clinical trial is feasible and acceptable to participants, particularly when embedded in trials. Reliable and valid findings can result, making patient self-reported outcomes a possible new trial endpoint. Cancer 2017;123:3799-3806. © 2017 American Cancer Society.
Assuntos
Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Fadiga/induzido quimicamente , Limitação da Mobilidade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Avaliação de Sintomas/métodos , Adolescente , Criança , Família , Estudos de Viabilidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Neoplasias/tratamento farmacológico , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Renal medullary carcinoma (RMC) was first described over two decades ago as the seventh sickle nephropathy. Survival after diagnosis with metastatic disease still rarely extends beyond 1 year, with recent reports of median overall survival in patients treated with platinum therapy being just 10 months. We describe our experience using platinum-based chemotherapy plus the proteasome inhibitor bortezomib to treat metastatic RMC in two pediatric patients who had complete responses. One patient passed away 7 years after diagnosis, while another remains disease free nearly 2 years from diagnosis.
Assuntos
Anemia Falciforme/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Medular/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adolescente , Bortezomib/administração & dosagem , Carcinoma Medular/etiologia , Carcinoma Medular/mortalidade , Criança , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/mortalidade , Masculino , Paclitaxel/administração & dosagem , GencitabinaRESUMO
BACKGROUND: Glomerular hyperfiltration has recently been reported in children with malignancies and has been attributed to increased solute from breakdown of tumor tissues. OBJECTIVE: To evaluate the prevalence of hyperfiltration in the pediatric oncology population and explore its pathophysiological mechanism. MATERIALS AND METHODS: Tc-99 m diethylenetriaminepentaacetic acid (DTPA) glomerular filtration rate (GFR) examinations (437 studies) and medical records of 177 patients <21 years of age diagnosed with a malignancy between January 2005 and October 2013 were retrospectively reviewed. Hyperfiltration was defined as a GFR ≥ 160 ml/min/1.73 m2. RESULTS: Seventy-seven (43.5%) patients had hyperfiltration in at least one GFR exam. A significantly higher percentage of patients with central nervous system (CNS) tumors (63.6%) had hyperfiltration when compared to other tumor types (27.3%, P < 0.001). No association was found between hyperfiltration and age, gender, race or bone marrow involvement. There was a significant trend toward decreasing hyperfiltration after the second cycle of chemotherapy (P = 0.006) and a significant increase in subjects with low GFR (<100 ml/min/1.73 m2) with increasing number of cycles of chemotherapy (P = 0.005). CONCLUSION: Glomerular hyperfiltration is common in children with malignancies at diagnosis and during initial cycles of chemotherapy. It is particularly prevalent in patients with central nervous tumors, which are frequently smaller in volume. Therefore, the pathophysiological mechanism of hyperfiltration cannot be explained solely on the basis of large tumor volume and subsequent cell breakdown. We hypothesize that host hypermetabolic state plays an important role in pathophysiology of hyperfiltration.
Assuntos
Taxa de Filtração Glomerular , Nefropatias/fisiopatologia , Neoplasias/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasias/tratamento farmacológico , Prevalência , Estudos Retrospectivos , Fatores de Risco , Pentetato de Tecnécio Tc 99m/análogos & derivadosRESUMO
Although solitary presentations of infantile myofibromatosis tend toward spontaneous regression, multicentric forms fare worse. Previous case reports have depicted observation, surgical resection, and systemic therapies as treatment options. This paper reports well-tolerated, successful outcomes in a series of patients with high-risk infantile myofibromatosis in need of life-sustaining interventions treated with a combination of vincristine and dactinomycin. The clinical presentation, pathology, and radiographic findings are described.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Miofibromatose/congênito , Dactinomicina/administração & dosagem , Humanos , Lactente , Recém-Nascido , Masculino , Miofibromatose/tratamento farmacológico , Prognóstico , Vincristina/administração & dosagemRESUMO
BACKGROUND: ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerization. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population. PROCEDURE: Children and adolescents (n = 91) with a median (range) age 7.7 (2.3-21.5) years and progressive neuroblastoma were enrolled and stratified by disease status into disease measureable by CT/MRI (n = 47) or disease assessable by (123) I-metaiodobenzylguanine scintigraphy (MIBG, n = 44). Response was evaluated using RECIST for measureable disease and the Curie score for MIBG-avid disease. RESULTS: ABT-751 was well tolerated. The objective response rate was 7%. The median TTP was 42 days (95% CI: 36, 56) in the measureable disease stratum and 45 days (95% CI: 42, 85) in the MIBG-avid disease stratum. TTP was similar to the historical control group (n = 136, median TTP 42 days). For the combined strata (n = 91), 1-year progression free survival (PFS) was 13 ± 4% and overall survival (OS) was 48 ± 5%. CONCLUSIONS: The low objective response rate and failure to prolong TTP indicate that ABT-751 is not sufficiently active to warrant further development for neuroblastoma. However, this trial demonstrates the utility of TTP as the primary endpoint in phase 2 trials in children and adolescents with neuroblastoma.
Assuntos
Antineoplásicos/uso terapêutico , Neuroblastoma/tratamento farmacológico , Terapia de Salvação , Sulfonamidas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Cápsulas , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Intervalo Livre de Doença , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Neuroblastoma/terapia , Qualidade de Vida , Recidiva , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Suspensões , Falha de TratamentoRESUMO
BACKGROUND: International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome. PROCEDURE: Of 8,800 patients in the INRG database, 1,483 with INSS Stage 3 neuroblastoma and complete follow-up data were analyzed. Secondary analysis was performed in 1,013 patients (68%) with MYCN-non-amplified (NA) tumors. Significant prognostic factors were identified via log-rank test comparisons of survival curves. Multivariable Cox proportional hazards regression model was used to identify factors independently predictive of event-free survival (EFS). RESULTS: Age at diagnosis (P < 0.0001), tumor MYCN status (P < 0.0001), and poorly differentiating/undifferentiated histology (P = 0.03) were independent predictors of EFS. Compared to other Stage 3 subgroups, outcome was inferior for patients ≥ 547 days with MYCN-NA neuroblastoma (P < 0.0001), and within this cohort, serum ferritin ≥ 96 ng/ml was associated with inferior EFS (P = 0.02). For patients <547 days of age with MYCN-NA tumors, serum ferritin levels were prognostic of overall survival (OS) (P = 0.04) and chromosome 11q aberration was prognostic of EFS (P = 0.03). CONCLUSIONS: Among patients with INSS Stage 3 neuroblastoma patients, age at diagnosis, MYCN status and histology predict outcome. Patients <547 days of age with MYCN-NA tumors that lack chromosome 11q aberrations or those with serum ferritin <96 ng/ml have excellent prognosis and should be considered for therapy reduction. Prospective clinical trials are needed to identify optimal therapy for those patients ≥ 547 days of age with undifferentiated histology or elevated serum ferritin.
Assuntos
Neuroblastoma/mortalidade , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Amplificação de Genes , Humanos , Lactente , Proteína Proto-Oncogênica N-Myc , Estadiamento de Neoplasias , Neuroblastoma/genética , Neuroblastoma/patologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Individuals with Neurofibromatosis type 1 (NF1) are at risk for developing malignant peripheral nerve sheath tumors (MPNST), which frequently arise in preexisting plexiform neurofibromas (PN). Magnetic resonance imaging (MRI) with volumetric analysis and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) were utilized to monitor symptomatic nodular lesions. PROCEDURE: Patients with NF1 and PN on a NCI natural history trial were monitored for total body tumor volume (TTV) using volumetric MRI. FDG-PET was performed in individuals with a nodular well-demarcated lesion ≥3 cm if they were growing, painful, or there was a prior history of MPNST (target lesions). Asymptomatic nodular lesions were evaluated as non-target lesions. RESULTS: Fifteen patients (8m, 7f) median age of 18.3 years (range, 10-45 years) had a single target and non-target (n = 46) nodular lesions identified on MRI. Target lesions arose within (n = 8) or outside (n = 3) a PN, and all but 1 had increased FDG uptake. FDG uptake was increased in non-target lesions but to a lesser degree. FDG uptake in the surrounding PN was low, similar to background activity. Pathologic evaluation performed in 11 patients demonstrated neurofibroma (n = 6), atypical neurofibroma (n = 2) and malignancy (n = 3). CONCLUSIONS: Nodular target lesions identified on MRI in individuals with NF1 and PN demonstrate increased FDG uptake similar to MPNST, but may be benign on biopsy. Nodular target lesions may be at greater risk for malignant transformation, but their biologic and clinical behavior has not been well studied. Careful longitudinal evaluation will be required to better understand the malignant potential of these lesions.
Assuntos
Fluordesoxiglucose F18 , Neoplasias de Bainha Neural/diagnóstico por imagem , Neurofibroma Plexiforme/diagnóstico por imagem , Neurofibromatose 1/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adolescente , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoAssuntos
Cefaleia/diagnóstico , Processo Mastoide/diagnóstico por imagem , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/terapia , Biópsia por Agulha , Quimioterapia Adjuvante , Criança , Terapia Combinada , Orelha/fisiopatologia , Feminino , Seguimentos , Cefaleia/etiologia , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética/métodos , Processo Mastoide/patologia , Mastoidectomia/métodos , Invasividade Neoplásica/patologia , Dor/diagnóstico , Dor/etiologia , Radioterapia Adjuvante , Sarcoma de Ewing/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Epithelioid sarcoma is a rare, high-grade malignant soft tissue tumor that is often misdiagnosed. Classified as a mesenchymal malignancy, it exhibits both mesenchymal and epithelial markers. Occurrence in children under age 10 is extremely rare. This report describes the clinical course and management of a 5-year-old girl who presented with epithelioid sarcoma in the distal extremity. The lesion was initially misdiagnosed and treated for over a year as a common wart.
RESUMO
BACKGROUND: ABT-751, an orally bioavailable sulfonamide, binds beta-tubulin to inhibit microtubule polymerization. We described response and event-free survival (EFS) in children with neuroblastoma and other solid tumors receiving ABT-751, assessed in vitro cytotoxicity of ABT-751 and evaluated the effect of ABT-751 on tubulin polymerization in peripheral blood mononuclear cells (PBMC) and pediatric tumor cell lines. PROCEDURE: Patients with neuroblastoma (n = 50) or other solid tumors (n = 26) enrolled on the ABT-751 pediatric phase I and pilot trials were reviewed. The sulforhodamine B (SRB) and ACEA Real-Time Cell Electronic Sensing (RT-CES) assays were used to determine the in vitro cytotoxicity. Pharmacodynamic effects on tubulin polymerization/depolymerization were assessed by Western blot and confocal microscopy using antibodies specific for post-translational modifications of polymerized tubulin. RESULTS: Forty-five patients with neuroblastoma were evaluated for anti-tumor response. No complete or partial responses were documented. The median EFS was 9.3 weeks for children with neuroblastoma and 3.3 weeks for children other solid tumors (P < 0.0001). The ABT-751 IC(50) was 0.6-2.6 mcM in neuroblastoma and 0.7-4.6 mcM in other solid tumor cell lines. Following drug exposure, polymerized tubulin decreased in a concentration- and time-dependent manner in cell lines. CONCLUSIONS: In children treated with ABT-751, the EFS is longer in children with neuroblastoma as compared to other diagnoses. In vitro, ABT-751 was cytotoxic at concentrations tolerable in children. Effects of ABT-751 on polymerization and microtubule structure were time- and dose-dependent but not dependent on tumor type.
Assuntos
Proliferação de Células/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Sulfonamidas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Tubulina (Proteína)/metabolismo , Adolescente , Linhagem Celular Tumoral , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Técnicas In Vitro , Masculino , Neuroblastoma/patologia , Projetos Piloto , Prognóstico , Sulfonamidas/farmacologia , Taxa de Sobrevida , Resultado do Tratamento , Moduladores de Tubulina/farmacologiaRESUMO
Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extra-cranial neoplasm of childhood. Variables with prognostic significance in patients with neuroblastoma, including age at diagnosis, disease stage, tumor histology, MYCN gene amplification, tumor cell ploidy, and the presence of segmental chromosomal aberrations are utilized to classify patients based on risk of disease recurrence. Patients with non-high-risk neuroblastoma, low- and intermediate-risk categories, represent nearly half of all newly diagnosed cases. This group has an excellent event-free and overall survival with current therapy. Over time, the objective in treatment of non-high-risk neuroblastoma has been reduction of therapy intensity to minimize short- and long-term adverse events all the while maintaining excellent outcomes.
RESUMO
PURPOSE: Infants with stage 4S neuroblastoma usually have favorable outcomes with observation or minimal chemotherapy. However, young infants with symptoms secondary to massive hepatomegaly or with unfavorable tumor biology are at high risk of death. Our aim was to improve outcomes for patients with symptomatic and/or unfavorable biology 4S neuroblastoma with a uniform treatment approach using a biology- and response-based algorithm. PATIENTS AND METHODS: The subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of histology, diploid DNA index, chromosome arm 1p or 11q loss of heterozygosity (LOH) status, and symptoms. RESULTS: Forty-nine eligible patients were enrolled: 41 were symptomatic and 28 had unfavorable biology. Seventeen patients (symptomatic, favorable biology) were assigned two cycles, 21 patients (any unfavorable biologic feature without 1p or 11q LOH) were assigned four cycles, and 11 patients (unfavorable biology including 1p and/or 11q LOH [n = 7] or symptomatic with unknown biology [n = 4]), were assigned eight cycles. The 3-year overall survival was 81.4% ± 5.8%. Eight of nine deaths were in patients younger than 2 months of age at diagnosis (median, 9 days [range, 1 to 68 days]): five acute deaths were a result of hepatomegaly and associated toxicities; two were a result of late relapse in patients with unfavorable biology; and two were a result of treatment complications. No deaths occurred after protocol-mandated pre-emptive treatment of infants younger than 2 months with hepatomegaly, regardless of symptoms. A new scoring algorithm for emergent chemotherapy in patients with 4S disease was developed on the basis of this experience. CONCLUSION: The outcome for 4S neuroblastoma can be improved with pre-emptive chemotherapy for evolving hepatomegaly or other baseline comorbidities in infants younger than 2 months of age.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neuroblastoma/diagnóstico , Neuroblastoma/tratamento farmacológico , Carboplatina/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Filgrastim/administração & dosagem , Amplificação de Genes , Hepatomegalia/patologia , Hepatomegalia/terapia , Humanos , Lactente , Recém-Nascido , Perda de Heterozigosidade , Masculino , Proteína Proto-Oncogênica N-Myc/genética , Estadiamento de Neoplasias , Neuroblastoma/genética , Neuroblastoma/patologia , Fatores de Risco , Taxa de SobrevidaRESUMO
PURPOSE: Tumor-associated antigen cytotoxic T cells (TAA-Ts) represent a new, potentially effective and nontoxic therapeutic approach for patients with relapsed or refractory solid tumors. In this first-in-human trial, we investigated the safety of administering TAA-Ts that target Wilms tumor gene 1, preferentially expressed antigen of melanoma, and survivin to patients with relapsed/refractory solid tumors. MATERIALS AND METHODS: TAA-T products were generated from autologous peripheral blood and infused over three dose levels: 1, 2, and 4 × 107 cells/m2. Patients were eligible for up to eight infusions administered 4 to 7 weeks apart. We assessed dose limiting toxicity during the first 45 days after infusion. Disease response was determined within the context of a phase I trial. RESULTS: There were no dose-limiting toxicities. Of 15 evaluable patients, 11 (73%) with stable disease or better at day 45 postinfusion were defined as responders. Six responders remain without progression at a median of 13.9 months (range, 4.1 to 19.9 months) after initial TAA-Ts. Patients who were treated at the highest dose level showed the best clinical outcomes, with a 6-month progression-free survival of 73% after TAA-T infusion compared with a 38% 6-month progression-free survival with prior therapy. Antigen spreading and a reduction in circulating tumor-associated antigens using digital droplet polymerase chain reaction was observed in patients after TAA-T infusion. CONCLUSION: TAA-Ts safely induced disease stabilization, prolonged time to progression, and were associated with antigen spreading and a reduction in circulating tumor-associated antigen DNA levels in patients with relapsed/refractory solid tumors without lymphodepleting chemotherapy before infusion. TAA-Ts are a promising new treatment approach for patients with solid tumors.
Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/transplante , Adolescente , Adulto , Antígenos de Neoplasias/imunologia , Criança , Pré-Escolar , Epitopos , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologiaRESUMO
PURPOSE: Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. METHODS: Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). RESULTS: Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was <5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated. CONCLUSIONS: Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.
Assuntos
Quinazolinas , Animais , Área Sob a Curva , Cloridrato de Erlotinib , Injeções Intravenosas , Macaca mulatta , Masculino , Taxa de Depuração Metabólica , Quinazolinas/administração & dosagem , Quinazolinas/sangue , Quinazolinas/líquido cefalorraquidianoRESUMO
We present a case of del(14)(q21) as a sole abnormality in a 4-year-old boy diagnosed with precursor B-cell acute lymphoblastic leukemia (pre-B ALL). To our knowledge, this is the first case of isolated del(14)(q21) in pre-B ALL. Two pretreatment bone marrow samples obtained 5 days apart were analyzed by cytogenetics. The G-banded karyotypes of the two samples were similar, differing only in the ratio of normal/abnormal metaphases detected. Both samples showed a del(14)(q21) as the only abnormality. Fluorescence in situ hybridization performed using the probes TEL/AML1 and immunoglobulin heavy chain (IGH) showed no fusion involving the TEL and AML1 genes and only a single IGH signal in 20% of the interphase cells analyzed.
Assuntos
Cromossomos Humanos Par 4/genética , Deleção de Genes , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , Rearranjo Gênico , Humanos , Cadeias Pesadas de Imunoglobulinas , Hibridização in Situ Fluorescente , Interfase , Cariotipagem , MasculinoRESUMO
BACKGROUND: B43-pokeweed antiviral protein (B43-PAP) is a high-affinity anti-CD19 immunotoxin that is capable of causing apoptotic death in B-lineage leukemic cells with a drug-resistant phenotype. B43-PAP exhibited in vivo antileukemic activity in preclinical studies as well as on a single-agent phase I clinical trial. This pediatric phase I/II study evaluated the toxicity profile and efficacy of B43-PAP immunotoxin in combination with standard induction chemotherapy in children and adolescents with relapsed CD19-positive B-lineage acute lymphoblastic leukemia (B-ALL). Pharmacokinetic profile and immunogenicity of B43-PAP were assessed. EXPERIMENTAL DESIGN: B43-PAP in combination with standard 3 and 4-drug induction chemotherapy was administered on days 9-13 and 21-25 of a 28-day treatment course with vincristine, prednisone, L-asparaginase, daunomycin, and intrathecal methotrexate. Thirty patients with relapsed B-ALL were enrolled on study CCG-0957. RESULTS: Grade III/IV nonhematologic dose-limiting toxicities were encountered in 4 patients evaluable for toxicity and included myalgias, motor dysfunction, pulmonary toxicity, and elevated liver transaminase. Dose-limiting toxicities occurred only with the 4-drug regimen. Fourteen patients achieved a complete remission at the end of induction among the 20 patients evaluable for response. CONCLUSIONS: B43-PAP in combination with standard induction chemotherapy can be safely administered and exhibits clinical antileukemic activity against relapsed B-ALL.
Assuntos
Antígenos CD19/imunologia , Antineoplásicos/uso terapêutico , Linfócitos B/imunologia , Imunotoxinas/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Proteínas Inativadoras de Ribossomos Tipo 1/imunologia , Adolescente , Anticorpos Monoclonais/imunologia , Criança , Pré-Escolar , Quimioterapia Combinada/métodos , Estudos de Viabilidade , Feminino , Humanos , Quimioterapia de Indução/métodos , MasculinoRESUMO
The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 microg/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 microg/m(2) of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.