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1.
Curr Treat Options Oncol ; 25(2): 176-190, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38324075

RESUMO

OPINION STATEMENT: Soft tissue sarcoma (STS), a substantial group of aggressive and rare tumors with tissue heterogeneity, is infrequently represented in clinical trials with an urgent necessity for newer treatment options. Lurbinectedin, an analog of trabectedin, is currently approved, in various countries, as a single agent, for the treatment of patients with relapsed small cell lung cancer (SCLC). However, preclinical and phase I and phase II trials have demonstrated the efficacy of lurbinectedin in different tumor types, including STS. The better understanding of the pathophysiology and evolution of STS as well as the mechanism of action of lurbinectedin in addition to the available data regarding the activity of this drug in this subset of patients will pave the way to newer therapeutic options and strategies.


Assuntos
Carbolinas , Compostos Heterocíclicos de 4 ou mais Anéis , Sarcoma , Neoplasias de Tecidos Moles , Tetra-Hidroisoquinolinas , Humanos , Tetra-Hidroisoquinolinas/uso terapêutico , Tetra-Hidroisoquinolinas/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Dioxóis/uso terapêutico , Dioxóis/farmacologia , Recidiva Local de Neoplasia/tratamento farmacológico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Neoplasias de Tecidos Moles/tratamento farmacológico
2.
Int J Cancer ; 138(4): 875-80, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26370299

RESUMO

Although a third of all cancers are diagnosed after the age of 75, only 9% of elderly people are recruited in clinical trials, because of fear of the risk of toxicity. The aim of this study was to compare the tolerance and efficacy observed in Phase I trials among patients aged over 75 years with that observed in younger patients. Patients treated from 2007 to 2012 at Institut Gustave Roussy in Phase I trials were included. The conditional Cox proportional hazards model was used to compare the occurrence of AE and overall survival in a subpopulation of elderly people (EP, aged >75 years) matched with patients aged <75 years (YP) according to the same Phase I protocol and the same Royal Marsden Hospital (RMH) prognostic score. Among the 32 EP and the 158 YP, 63% and 61% experienced Grade 3-4 AEs and dose-limiting toxicities occurred in 6% and 11% in each group respectively. Age over 75 years was neither associated with a greater risk of high toxicity (HR=0.90 [CI95%, 0.47-1.70], p = 0.74) nor of death (HR=0.86; CI95%: 0.38-1.93; p = 0.71). Age over 75 years had no impact on the occurrence of either high toxicity or of death.


Assuntos
Antineoplásicos/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Sujeitos da Pesquisa/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais
3.
Anticancer Drugs ; 27(10): 1021-7, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27610894

RESUMO

This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m, n=3; 3.8 mg/m, n=4; and 4.8 mg/m, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/farmacocinética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Depsipeptídeos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Peptídeos Cíclicos , Estudos Prospectivos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo
4.
Oncologist ; 20(3): 245-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25669662

RESUMO

BACKGROUND: This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. METHODS: In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. RESULTS: Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. CONCLUSION: Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Quinazolinas/administração & dosagem , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Relação Dose-Resposta a Droga , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Quinazolinas/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Resultado do Tratamento
5.
Cancer Treat Rev ; 123: 102675, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38159438

RESUMO

Desmoid tumors (DT) are rare, slow-growing, locally invasive soft tissue tumors that often pose significant therapeutic challenges. Traditional management strategies including active surveillance, surgery, radiotherapy, and systemic therapy which are associated with varying recurrence rates and high morbidity. Given the challenging nature of DT and the modest outcomes associated with current treatment strategies, there has been a growing interest in the field of γ-secretase inhibitors as a result of its action on the Wnt/ß-catenin signaling pathway. In this review article, we will shed the light on the pathogenesis and molecular biology of DT, discuss its symptoms and diagnosis, and provide a comprehensive review of the traditional therapeutic approaches. We will also delve into the mechanisms of action of γ-secretase inhibitors, its efficacy, and the existing preclinical and clinical data available to date on the use of these agents, as well as the potential challenges and future prospects in the treatment landscape of these tumors.


Assuntos
Fibromatose Agressiva , Humanos , Fibromatose Agressiva/tratamento farmacológico , Fibromatose Agressiva/patologia , Secretases da Proteína Precursora do Amiloide/uso terapêutico
6.
ACS Nano ; 18(26): 16516-16529, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38912600

RESUMO

Activated guided irradiation by X-ray (AGuIX) nanoparticles are gadolinium-based agents that have the dual benefit of mimicking the effects of a magnetic resonance imaging (MRI) contrast agent used in a clinical routine and enhancing the radiotherapeutic activity of conventional X-rays (for cancer treatment). This "theragnostic" action is explained on the one hand by the paramagnetic properties of gadolinium and on the other hand by the generation of high densities of secondary radiation following the interaction of ionizing radiation and high-Z atoms, which leads to enhanced radiation dose deposits within the tumors where the nanoparticles accumulate. Here, we report the results of a phase I trial that aimed to assess the safety and determine the optimal dose of AGuIX nanoparticles in combination with chemoradiation and brachytherapy in patients with locally advanced cervical cancer. AGuIX nanoparticles were administered intravenously and appropriately accumulated within tumors on a dose-dependent manner, as assessed by T1-weighted MRI, with a rapid urinary clearance of uncaught nanoparticles. We show that the observed tumor accumulation of the compounds can support precise delineation of functional target volumes at the time of brachytherapy based on gadolinium enhancement. AGuIX nanoparticles combined with chemoradiation appeared well tolerated among the 12 patients treated, with no dose-limiting toxicity observed. Treatment yielded excellent local control, with all patients achieving complete remission of the primary tumor. One patient had a distant tumor recurrence. These results demonstrate the clinical feasibility of using theranostic nanoparticles to augment the accuracy of MRI-based treatments while focally enhancing the radiation activity in tumors.


Assuntos
Gadolínio , Imageamento por Ressonância Magnética , Nanopartículas , Neoplasias do Colo do Útero , Gadolínio/química , Humanos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/patologia , Feminino , Nanopartículas/química , Pessoa de Meia-Idade , Braquiterapia , Meios de Contraste/química , Raios X , Adulto , Idoso , Quimiorradioterapia
7.
Invest New Drugs ; 31(3): 623-30, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22688291

RESUMO

PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Tetra-Hidroisoquinolinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/farmacocinética , Adulto Jovem
8.
Onkologie ; 36(6): 357-62, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23774150

RESUMO

AIM: To analyze the clinical features and outcomes of advanced non-small cell lung cancer (NSCLC) patients treated in phase I trials. PATIENTS AND METHODS: The clinical characteristics, efficacy and toxicity data of 70 pretreated NSCLC patients enrolled in 17 phase I trials between January 2005 and June 2010 were analyzed at our institution. RESULTS: The histological types were: adenocarcinoma (79%), squamous cell carcinoma (13%), and others. Patients received a median number of 3 prior lines of treatment before inclusion. 1 complete response (CR), 11 (16%) partial responses (PRs), and 29 (41%) stable diseases (SDs) were observed (according to Response Evaluation Criteria in Solid Tumors (RECIST)). The median overall survival (OS) time was 18 months and the median progression-free survival (PFS) time was 4.1 months. The median PFS of these patients within their prior therapy line before phase I inclusion was 4.3 months. A performance status score of 0 and the number of prior lines of treatment were significant for OS and PFS in multivariate analysis, respectively. Grade 3/4 toxicities were observed in 20 (27%) patients, and there was 1 treatment-related death. CONCLUSION: Patients in good general condition and with limited pretreatment derived an improved benefit, suggesting that phase I studies may be a valid option for pretreated NSCLC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Medicina Baseada em Evidências , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Idoso , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
9.
Eur J Cancer ; 188: 1-7, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37178645

RESUMO

BACKGROUND: Phase I trials historically involved heavily pretreated patients (pts) with no more effective therapeutic options available and with poor expected outcomes. There are scare data regarding profile and outcomes of pts enrolled into modern phase I trials. Here, we sought to provide an overview of pts' profile and outcome into phase I trials at Gustave Roussy (GR). METHODS: This is a monocentric retrospective study, including all pts enrolled into phase I trials at GR from 2017 to 2021. Data regarding pts' demographics, tumour types, investigational treatments and survival outcomes were collected. RESULTS: In total, 9482 pts were referred for early phase trials; 2478 pts were screened, among which 449 (18.1%) failed screening; 1693 pts finally received at least one treatment dose as part of a phase I trial. Median age of pts was 59 years old (range, 18-88) and most common tumour types included gastrointestinal (25.3%), haematological (15%), lung (13.6%), genitourinary (10.5%) and gynaecologic cancers (9.4%). Amongst all pts treated and evaluable for response (1634 pts), objective response rate was 15.9% and disease control rate was 45.4%. Median progression-free survival and overall survival were, respectively, 2.6 months (95% confidence interval [95% CI], 2.3; 2.8) and 12.4 months (95% CI, 11.7; 13.6). CONCLUSION: As compared with historical data, our study shows that outcomes of pts included into modern phase I trials have improved and that these trials constitute nowadays a valid and safe therapeutic option. These updated data provide facts for adapting the methodology, role and place of phase I trials over the next years.


Assuntos
Neoplasias , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
10.
Oral Oncol ; 125: 105715, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35030408

RESUMO

Effective treatments are scarce in non-operable scalp cutaneous angiosarcoma patients. Curative-intent definitive sequential IMRT and plesiobrachytherapy allowed complete response with limited side effect in two elder patients. This could represent a non-invasive therapeutic option for patients with locally advanced presentation.


Assuntos
Braquiterapia , Hemangiossarcoma , Radioterapia de Intensidade Modulada , Neoplasias Cutâneas , Idoso , Hemangiossarcoma/radioterapia , Humanos , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Couro Cabeludo , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/radioterapia
11.
Clin Cancer Res ; 24(7): 1536-1545, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29217526

RESUMO

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies.Experimental Design: Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control.Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation.Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536-45. ©2017 AACR.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas de Transporte Vesicular/antagonistas & inibidores , Adulto , Idoso , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Neoplasias do Colo/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Neoplasias Renais/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico
12.
Leuk Res ; 39(2): 157-63, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25530567

RESUMO

The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination.


Assuntos
Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Tontura/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/enzimologia , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos
13.
Bull Cancer ; 102(2): 174-81, 2015 Feb.
Artigo em Francês | MEDLINE | ID: mdl-25609484

RESUMO

Communication training programs in oncology have demonstrated some efficacy to improve doctors' communication skills. The goal of our study was to evaluate the impact of such training in the particular context of phase I clinical trials. Self-satisfaction and self-efficacy scales evaluating doctor-patient communication was completed by 6 medical oncologists (3 juniors and 3 seniors) before and after their communication training for a total of sixty visits. Two types of visit have been distinguished: the visits between the oncologist and the patient alone (a dual situation) and those with a third party (a trilateral situation). For all the doctors in dual and trialateral situations, self-efficacy scores improved significantly after training. This improvement was more pronounced for juniors oncologists in trilateral situations. Before training, satisfactory scores were worst in duel versus trilateral situations (P=0.01). This was particularly pronounced for junior compared to senior doctors (P=0.035). After training, in trilateral situations, the satisfaction scores of junior doctors matched that of the senior doctors. The communication training programs appear to benefit junior oncologists to a greater extent in trilateral situations.


Assuntos
Ensaios Clínicos Fase I como Assunto , Comunicação , Acompanhantes Formais em Exames Físicos , Oncologia/educação , Corpo Clínico/psicologia , Relações Médico-Paciente , Autoeficácia , Humanos , Satisfação Pessoal
14.
Oncoimmunology ; 2(2): e23079, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23525192

RESUMO

Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation.

15.
Eur J Cancer ; 47(17): 2512-6, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21763126

RESUMO

PURPOSE: The evaluation of treatment efficacy with RECIST criteria does not take into account tumour growth dynamics. We notably investigated the impact of the pre-treatment tumour growth rate (GR) on the evaluation of treatment response. PATIENTS AND METHODS: Seventy-six patients included in phase I clinical trials had scanographic evaluations before and after starting an experimental treatment. The GR was calculated for the pre-treatment period and for the experimental period (i.e. during the new treatment). Tumour response was evaluated per protocol at week 12 and at week 24 of the experimental period according to RECIST criteria. We studied the relation between pre-treatment and experimental GRs and RECIST tumour response. RESULTS: On average the tumour GR was decreased by 40% during the experimental period; compared to the pretreatment period (p=0.03). An increased growth rate (acceleration of GR during experimental treatment compared to pretreatment) was observed in 20 (38%) of the 53 patients considered as non-progressive at week 12 according to RECIST. Conversely a decreased GR was observed in 12 out of 23 (53%) patients classified as progressive according to RECIST. The variation in the GR between the pre-treatment and experimental period was not significantly correlated with response evaluated according to RECIST at week 12 or at week 24 (p=0.45 and 0.44, respectively). CONCLUSIONS: RECIST evaluation of tumour response depends on the natural history of the tumours and poorly measures the impact of treatment on the kinetics of tumour growth. Integrating pre-treatment GR evaluations could substantially improve the assessment of treatment efficacy in drug development.


Assuntos
Ensaios Clínicos Fase I como Assunto/métodos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Progressão da Doença , Estudos de Viabilidade , Feminino , Humanos , Masculino , Carga Tumoral
16.
Clin Lung Cancer ; 10(5): 364-6, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19808196

RESUMO

Pemetrexed is a structurally novel antifolate agent approved in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma who have unresectable disease and for the therapy of previously treated patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) as a single agent or in association with cisplatin as a first-line treatment in patients with nonsquamous histology. Herein, we report a case of pemetrexed-induced pneumonitis. Because pemetrexed is being prescribed with increasing frequency for NSCLC and mesothelioma, we believe that physicians should be aware of this rare but serious complication.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hipersensibilidade a Drogas/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pneumonia/diagnóstico , Nódulo Pulmonar Solitário/tratamento farmacológico , Corticosteroides/administração & dosagem , Idoso , Anti-Infecciosos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Ciprofloxacina/administração & dosagem , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Hipersensibilidade a Drogas/patologia , Hipersensibilidade a Drogas/fisiopatologia , Quimioterapia Combinada , Dispneia , Eritema , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Recidiva Local de Neoplasia , Paclitaxel/administração & dosagem , Pemetrexede , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia/fisiopatologia , Fibrose Pulmonar , Recuperação de Função Fisiológica , Nódulo Pulmonar Solitário/diagnóstico , Nódulo Pulmonar Solitário/patologia , Nódulo Pulmonar Solitário/fisiopatologia
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