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1.
J Clin Oncol ; 42(13): 1488-1498, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38315944

RESUMO

PURPOSE: Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. METHODS: A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. RESULTS: Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. CONCLUSION: Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.


Assuntos
Mutação , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Trabectedina , Humanos , Feminino , Trabectedina/uso terapêutico , Trabectedina/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Idoso , Adulto , Recidiva Local de Neoplasia/tratamento farmacológico , Fenótipo , Estudos Prospectivos , Proteína BRCA2/genética , Proteína BRCA1/genética , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão
2.
JAMA Oncol ; 9(5): 656-663, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36995731

RESUMO

Importance: Preclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring. Objective: To explore the effectiveness and safety of trabectedin combined with RT. Design, Setting, and Participants: This international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall. Interventions: Trabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment. Main Outcomes and Measures: The primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response. Results: A total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated. Conclusions and Relevance: Although the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.


Assuntos
Lipossarcoma Mixoide , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Masculino , Feminino , Trabectedina/efeitos adversos , Trabectedina/administração & dosagem , Lipossarcoma Mixoide/tratamento farmacológico , Lipossarcoma Mixoide/radioterapia , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico
3.
Cancer Res ; 82(4): 708-720, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34903601

RESUMO

Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. Patients are treated according to Ewing sarcoma protocols, but CDS-specific therapies are strongly needed. In this study, RNA sequencing was performed on patient samples to identify a selective signature that differentiates CDS from Ewing sarcoma and other fusion-driven sarcomas. This signature was used to validate the representativeness of newly generated CDS experimental models-patient-derived xenografts (PDX) and PDX-derived cell lines-and to identify specific therapeutic vulnerabilities. Annotation analysis of differentially expressed genes and molecular gene validation highlighted an HMGA2/IGF2BP/IGF2/IGF1R/AKT/mTOR axis that characterizes CDS and renders the tumors particularly sensitive to combined treatments with trabectedin and PI3K/mTOR inhibitors. Trabectedin inhibited IGF2BP/IGF2/IGF1R activity, but dual inhibition of the PI3K and mTOR pathways was required to completely dampen downstream signaling mediators. Proof-of-principle efficacy for the combination of the dual AKT/mTOR inhibitor NVP-BEZ235 (dactolisib) with trabectedin was obtained in vitro and in vivo using CDS PDX-derived cell lines, demonstrating a strong inhibition of local tumor growth and multiorgan metastasis. Overall, the development of representative experimental models (PDXs and PDX-derived cell lines) has helped to identify the unique sensitivity of the CDS to AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer. SIGNIFICANCE: This study identifies altered HMGA2/IGF2BP/IGF2 signaling in CIC-DUX4 sarcomas and provides proof of principle for combination therapy with trabectedin and AKT/mTOR dual inhibitors to specifically combat the disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Sarcoma/genética , Sarcoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismo , Trabectedina/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
Future Oncol ; 17(21s): 7-10, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34107768

RESUMO

Sarcoma oncologists face many uncertainties which can threaten the benefit/risk balance during early management of patients with advanced or metastatic soft tissue sarcoma. This point is illustrated by a clinical case involving an elderly patient with comorbidities and a diagnosis of metastatic leiomyosarcoma. The patient was not a candidate for doxorubicin-based chemotherapy because of his cardiac history and was hesitant about systemic chemotherapy, ultimately expressing a preference for a well-tolerated regimen. After evaluating the treatment alternatives, trabectedin was chosen based on its indication for use in persons unsuited to receive anthracyclines and evidence supporting its efficacy and safety in elderly patients. The patient received 17 cycles of trabectedin for a best response of stable disease with good quality of life.


Assuntos
Quimiorradioterapia/efeitos adversos , Leiomiossarcoma/terapia , Neoplasias Pulmonares/terapia , Neoplasias da Coluna Vertebral/terapia , Trabectedina/efeitos adversos , Idoso de 80 Anos ou mais , Quimiorradioterapia/métodos , Progressão da Doença , Evolução Fatal , Humanos , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/secundário , Vértebras Lombares/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Medição de Risco , Neoplasias da Coluna Vertebral/diagnóstico , Neoplasias da Coluna Vertebral/secundário , Trabectedina/administração & dosagem
5.
Cancer Med ; 10(11): 3565-3574, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33960681

RESUMO

BACKGROUND: As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment. METHODS: Patient data for multiple cardiac-related treatment-emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231). RESULTS: Multivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24-2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12-2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75-4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16-3.05]; p = 0.010). CONCLUSIONS: For patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Doxorrubicina/análogos & derivados , Coração/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Sarcoma/tratamento farmacológico , Trabectedina/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiotoxicidade , Doenças Cardiovasculares/diagnóstico , Criança , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Vigilância de Produtos Comercializados , Estudos Retrospectivos , Neoplasias de Tecidos Moles/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Trabectedina/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Adulto Jovem
6.
Clin Lung Cancer ; 22(4): 361-370.e3, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-32732073

RESUMO

INTRODUCTION: New therapeutic approaches in unresectable malignant pleural mesothelioma (MPM) are eagerly awaited. Trabectedin is an antitumor agent with an effect on cancer cell proliferation and a modulating action on tumor microenvironment. The ATREUS study explored the activity and safety of trabectedin in patients with unresectable MPM. METHODS: Epithelioid patients with MPM received trabectedin as second-line while biphasic/sarcomatoid patients with MPM as first- or second-line therapy. Treatment was given intravenously at an initially planned dose of 1.3 mg/m2 every 3 weeks, until progression or unacceptable toxicity. The primary endpoint was progression-free survival rate at 12 weeks (PFS12wks). RESULTS: Overall, 78 patients (54%) had epithelioid and 67 (46%) nonepithelioid MPM. PFS12wks in 62 evaluable patients with epithelioid MPM was 43.5% (80% confidence interval 34.9%-52.5%); median progression-free and overall survival were 2.4 and 9.0 months, respectively. PFS12wks in 52 evaluable patients with nonepithelioid MPM was 30.8% (90% confidence interval 20.3%-42.9%); median progression-free and overall survival were 1.7 and 5.4 months. Trabectedin starting dose was amended due to excess of liver toxicity. Eighty-four (64%) and 48 (36%) patients received 1.3 mg/m2 and 1.1. mg/m2, respectively. The most common grade 3-4 toxicities were hepatotoxicity, leukopenia/neutropenia, and fatigue. Grade 3-4 hepatotoxicity was reported in 59 (70%) patients treated at 1.3 mg/m2, and in 19 (40%) treated at 1.1 mg/m2. CONCLUSIONS: Trabectedin showed modest clinical activity, at the expense of relevant liver toxicity. Further development of this drug in MPM at full doses is not warranted.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Mesotelioma Maligno/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Trabectedina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Humanos , Masculino , Mesotelioma Maligno/patologia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão , Taxa de Sobrevida , Trabectedina/efeitos adversos , Resultado do Tratamento , Microambiente Tumoral
7.
Future Oncol ; 17(3s): 9-19, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33353406

RESUMO

Following the failure of first-line platinum-based chemotherapy in ovarian cancer, options for further therapy in potentially platinum-responsive patients are: carboplatin doublets with pegylated liposomal doxorubicin, gemcitabine or paclitaxel in association with bevacizumab, followed by maintenance with bevacizumab (for nonpretreated patients); or maintenance monotherapy with a poly(ADP-ribose) polymerase inhibitor after a response. The choice of biological therapy depends on a patient's previous treatments and priority for a symptomatic response. In cases of a rapidly growing tumor or need for symptomatic relief, the addition of bevacizumab should be considered. Patients with limited potential sensitivity to platinum, such as those with a platinum treatment-free interval of 6-12 months, may benefit from intercalation with trabectedin and pegylated liposomal doxorubicin to possibly restore platinum sensitivity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Trabectedina/uso terapêutico , Adulto , Carboplatina/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Trabectedina/administração & dosagem
8.
Expert Rev Anticancer Ther ; 20(11): 957-963, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32930637

RESUMO

INTRODUCTION: The efficacy and tolerability of trabectedin in patients with soft tissue sarcoma (STS) have been confirmed by various clinical studies involving lipo- and leiomyosarcomas as well as many other subtypes including translocation-related sarcomas. These data have been obtained from randomized phase II and III clinical trials. Studies in real-world clinical practice are necessary to bridge the efficacy-effectiveness gap and complete the body of evidence. Furthermore, reinforcing clinical experience with data from routine clinical practice allows drug management to be optimized and clinical benefits to be maximized. AREAS COVERED: The present review provides the most significant data on the efficacy of trabectedin in real-world studies, and the interpretation of real-world experience with trabectedin, in patients with advanced STS. EXPERT OPINION: Trabectedin has demonstrated durable disease control and an adequate safety profile, indicating it to be a suitable long-term treatment drug associated with a good quality of life. Personalized strategies and individualized objectives are the way forward in the management of STS.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Sarcoma/tratamento farmacológico , Trabectedina/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Humanos , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/patologia , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcoma/patologia , Trabectedina/efeitos adversos
9.
Anticancer Res ; 40(7): 3939-3945, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620635

RESUMO

BACKGROUND: Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice. PATIENTS AND METHODS: Patients with ROC after at least one platinum-based regimen received 1.1 mg/m2 trabectedin plus 30 mg/m2 PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)]. RESULTS: Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups. CONCLUSION: Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Trabectedina/administração & dosagem
10.
Acta Oncol ; 59(9): 1084-1090, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32400254

RESUMO

Purpose: Overall prognosis of advanced sarcoma remains poor, optimization of systemic treatment is urgently needed in this setting.Materials and methods: We systematically reviewed fully published English-speaking literature about maintenance therapy and drug holiday in sarcoma patients management.Results: We found that switch maintenance therapy with cyclophosphamide/vinorelbine improves the outcome of localized high-risk rhabdomyosarcoma. There is no other maintenance therapy recommended in sarcoma patients. After classical chemotherapy, maintenance therapy with immune-stimulating agents for localized osteosarcoma, bevacizumab for advanced angiosarcoma or pediatric advanced sarcoma, or mTOR inhibitors for metastatic sarcoma does not improve the outcome. Drug holiday has been assessed for metastatic gastrointestinal stromal tumor treated with imatinib as the first-line therapy or for metastatic soft-tissue sarcoma treated with trabectedin. Drug holiday has been found to lead to rapid disease progression and should be avoided.Conclusions: Data about both maintenance and drug holiday are spare in sarcoma management.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hemangiossarcoma/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Osteossarcoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Substituição de Medicamentos , Hemangiossarcoma/diagnóstico , Hemangiossarcoma/mortalidade , Humanos , Quimioterapia de Manutenção/efeitos adversos , Osteossarcoma/diagnóstico , Osteossarcoma/mortalidade , Prognóstico , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/mortalidade , Taxa de Sobrevida , Trabectedina/administração & dosagem , Trabectedina/efeitos adversos , Vinorelbina/administração & dosagem , Vinorelbina/efeitos adversos
11.
Expert Rev Anticancer Ther ; 20(sup1): 15-28, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32349558

RESUMO

Introduction: Although rapid evolution over the past few years in advanced soft tissue sarcoma (STS) management has not been without its challenges, it has brought clarity in several areas.Areas covered: This article summarizes the proceedings of the third edition of the Soft Tissue Sarcoma: Evidence and Experience symposium held March 2019 in Madrid, Spain. An update is provided of current approaches to advanced STS management. Case studies illustrate the role of trabectedin in advanced STS management.Expert opinion: First-line treatment of advanced STS requires distinct therapeutic strategies depending on goal: tumor shrinkage or tumor control. Since all sarcoma patients benefit from active treatment irrespective of age or line of therapy, oncologists have a duty to offer active systemic therapies unless the patient is unfit for treatment or chooses to end active treatment. Beyond the first line, histology becomes increasingly relevant for treatment selection. Agents with activity in specific sarcoma subtypes have been identified. Rare tumors represent a substantial medical need requiring strong international collaboration between research groups, pharmaceutical companies, regulatory agencies, and patients to identify active drugs per subtype. Multidisciplinary care in an expert sarcoma center is the primary means of reducing morbidity and mortality in patients with sarcoma.


Assuntos
Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia , Animais , Antineoplásicos Alquilantes/administração & dosagem , Humanos , Cooperação Internacional , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Trabectedina/administração & dosagem
12.
Anticancer Drugs ; 31(8): 799-805, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32304410

RESUMO

Antibody-cytokine fusion proteins (also called 'immunocytokines') represent an emerging class of biopharmaceutical products, which are being considered for cancer immunotherapy. When used as single agents, pro-inflammatory immunocytokines are rarely capable of inducing complete and durable cancer regression in mouse models and in patients. However, the combination treatment with conventional chemotherapy or with other immune-stimulatory agents typically increases the therapeutic efficacy of immunocytokines. In this article, we describe combination treatments of a tumor-targeting antibody-cytokine fusion protein based on the L19 antibody (specific to a splice isoform of fibronectin) fused to murine tumor necrosis factor with standard chemotherapy (dacarbazine, trabectedin or melphalan) or with an immune check-point inhibitor (anti-PD-1) in a BALB/c derived immunocompetent murine model of sarcoma (WEHI-164). All combination treatments led to improved tumor remission compared to single-agent treatments, suggesting that these combination partners may be suitable for further clinical development in sarcoma patients.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/administração & dosagem , Sarcoma/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Dacarbazina/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/administração & dosagem , Sarcoma/imunologia , Sarcoma/patologia , Trabectedina/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Pharm Biomed Anal ; 185: 113261, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32229403

RESUMO

Few time-consuming bioanalytical methods are currently available for trabectedin quantification in clinical investigations. Here we present a novel, fast and sensitive method for trabectedin determination in human plasma based on hydrophilic interaction liquid chromatography and tandem mass spectrometry (HILIC-MS/MS). Plasma samples are treated with acetonitrile-0.1 % formic acid and the solvent extract is directly injected into an Acquity BEH Amide column (2.1 × 100 mm, 1.7 µm) operating in HILIC mode at 0.2 mL/min with 80:20 acetonitrile-0.1 % formic acid in water. The analyte is separated by an organic solvent gradient and quantified by an Agilent Ultivo triple quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) mode. The quantitative MRM transitions were m/z 762→234 and m/z 765→234 for trabectedin and its d3-labeled derivative, respectively. The lower limit of quantification (LLOQ) was 0.01 ng/mL and the assay was linear up to 2.5 ng/mL. The intra- and inter-day relative error ranged from 1.19 % to 8.52 %, while the relative standard deviation was less than 12.35 %. The method was used to determine the pharmacokinetic profiles of trabectedin in 26 patients with soft tissue sarcoma, showing that this new HILIC-MS/MS method is suitable for use in clinical research.


Assuntos
Antineoplásicos Alquilantes/sangue , Monitoramento de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Sarcoma/tratamento farmacológico , Trabectedina/sangue , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Limite de Detecção , Reprodutibilidade dos Testes , Sarcoma/sangue , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo , Trabectedina/administração & dosagem , Trabectedina/química , Trabectedina/farmacocinética
14.
JAMA Oncol ; 6(4): 535-541, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32077895

RESUMO

Importance: Active therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival. Objective: To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas. Design, Setting, and Participants: Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 as dose level -1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population. Interventions: Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2). Main Outcomes and Measures: The dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas. Results: Eighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment. Conclusions and Relevance: The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas. Trial Registration: ClinicalTrials.gov Identifier: NCT02275286.


Assuntos
Sarcoma/tratamento farmacológico , Sarcoma/radioterapia , Trabectedina/administração & dosagem , Adulto , Idoso , Terapia Combinada , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , França/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Sarcoma/patologia , Espanha/epidemiologia , Trabectedina/efeitos adversos
15.
Gynecol Oncol ; 156(3): 535-544, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31924332

RESUMO

OBJECTIVE: This phase 3 study aimed to compare overall survival (OS) of women with platinum-sensitive, recurrent ovarian cancer (ROC) treated with third-line trabectedin (T) + pegylated liposomal doxorubicin (PLD) vs. PLD monotherapy. METHODS: Women with advanced-relapsed epithelial ovarian cancer were randomly assigned 1: 1 to intravenous infusions of either T + PLD (trabectedin 1.1 mg/m2 for 3 h; PLD 30 mg/m2 for 1.5 h, every 3 weeks) or PLD (50 mg/m2 for 1.5 h, every 4 weeks). Primary endpoint was OS. Secondary endpoints included investigator-assessed progression free survival (PFS) and objective response rates (ORR). At randomization, patients were stratified by time from last dose of first-line platinum therapy to disease progression, ECOG grade 0 or 1, BRCA1/2 germline mutational status, and prior PLD therapy. Exploratory endpoints included OS, PFS, and ORR in the stratified subgroups (PFI, ECOG, BRCA1/2 status, and prior PLD therapy). This trial is registered with ClinicalTrials.gov, number NCT01846611. RESULTS: 576 patients were randomized (T + PLD, n = 289; PLD, n = 287). Median OS was 23.8 months with T + PLD vs. 22.2 months with PLD (HR:0.92, 95%CI:0.73-1.18; p = 0.52). Median PFS was 7.52 vs. 7.26 months (HR:0.93, 95%CI:0.76-1.15; p = 0.52); ORR was 46% vs. 35.9% (OR:1.52, 95%CI:1.07-2.16; p = 0.01). Patients with BRCA1/2 mutations had median OS of 34.2 months with T + PLD vs. 20.9 months with PLD (HR:0.54, 95%CI:0.33-0.90; p = 0.016). Patients with BRCA1/2 mutations had median PFS of 10.1 months with T + PLD vs. 7.6 months with PLD (HR:0.72, 95%CI:0.48-1.08; p = 0.039). Patients with BRCA1/2 mutations and a 6-12 months platinum-free interval (PFI), median OS was 31.5 vs. 14.9 months, respectively (HR:0.37, 95%CI:0.17-0.82; p = 0.011). Grade 3-4 AEs were higher in T + PLD (79%) vs. PLD (54%). CONCLUSION: Combination of T and PLD did not show favorable OS benefit nor safety; however, patients with germline BRCA1/2 mutations and/or a PFI of 6-12 months appear to have clinically relevant survival benefit with T + PLD. No new safety signals were identified.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Intervalo Livre de Progressão , Taxa de Sobrevida , Trabectedina/administração & dosagem , Trabectedina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
16.
Anticancer Res ; 39(12): 6463-6470, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810910

RESUMO

BACKGROUND/AIM: The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model. MATERIALS AND METHODS: A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week. RESULTS: All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group. CONCLUSION: These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Trabectedina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Peso Corporal/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Neoplasias Colorretais/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Leucovorina/administração & dosagem , Leucovorina/farmacologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Distribuição Aleatória , Trabectedina/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Anticancer Res ; 39(11): 5999-6005, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704825

RESUMO

BACKGROUND/AIM: In the present study, we aimed to determine the efficacy of trabectedin (TRAB) combined with oxaliplatinum (OXA)+5-fluorouracil (5-FU) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: A patient CRC tumor previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice. Harvested tumor fragments were transplanted orthotopically in non-transgenic nude mice. Mice were randomized into three groups: Group 1 (G1), untreated-control; Group 2 (G2), OXA+5-FU; Group 3 (G3), TRAB+OXA+5-FU. Tumor width, length, and mouse body weight were measured twice a week. RESULTS: Both treatment groups inhibited tumor growth compared to the untreated control group. The combination of TRAB, OXA and 5-FU was significantly more efficacious than OXA+5-FU and arrested tumor growth. No significant changes were observed in body-weight in any of the three groups. CONCLUSION: TRAB, OXA and 5-FU combination has clinical potential for this and other CRC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Modelos Animais de Doenças , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias Colorretais/patologia , Fluoruracila/administração & dosagem , Humanos , Camundongos , Camundongos Nus , Oxaliplatina/administração & dosagem , Trabectedina/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Br J Cancer ; 121(9): 744-750, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31537908

RESUMO

BACKGROUND: Trabectedin, in addition to its antiproliferative effect, can modify the tumour microenvironment and this could be synergistic with bevacizumab. The efficacy and safety of trabectedin and bevacizumab ± carboplatin have never been investigated. METHODS: In this phase 2 study, women progressing between 6 and 12 months since their last platinum-based therapy were randomised to Arm BT: bevacizumab, trabectedin every 21 days, or Arm BT+C: bevacizumab, trabectedin and carboplatin every 28 days, from cycles 1 to 6, then trabectedin and bevacizumab as in Arm BT. Primary endpoints were progression-free survival rate (PFS-6) and severe toxicity rate (ST-6) at 6 months, assuming a PFS-6 ≤35% for BT and ≤40% for BT+C as not of therapeutic interest and, for both arms, a ST-6 ≥ 30% as unacceptable. RESULTS: BT+C (21 patients) did not meet the safety criteria for the second stage (ST-6 45%; 95%CI: 23%-69%) but PFS-6 was 85% (95%CI: 62%-97%). BT (50 patients) had 75% PFS-6 (95%CI: 60%-87%) and 16% ST-6 (95%CI 7%-30%). CONCLUSIONS: BT compared favourably with other platinum- and non-platinum-based regimens. The combination with carboplatin needs to be assessed further in a re-modulated safer schedule to confirm its apparent strong activity. CLINICAL TRIAL REGISTRATION: NCT01735071 (Clinicaltrials.gov).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Taxa de Sobrevida , Trabectedina/administração & dosagem , Trabectedina/efeitos adversos
19.
In Vivo ; 33(5): 1609-1614, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471412

RESUMO

BACKGROUND/AIM: Trabectedin is a synthetic antineoplastic agent approved for advanced soft tissue sarcoma (STS) in Japan. The aim of this study was to evaluate the efficacy and safety of the Japan-approved dose of trabectedin for advanced STS. PATIENTS AND METHODS: We retrospectively reviewed 38 patients with advanced STS who received salvage chemotherapy with trabectedin. RESULTS: The overall response and disease control rates were 16% (5 patients) and 67% (20 patients), respectively. The median progression-free and overall survival were 7.3 and 17.8 months, respectively. There were no significant differences between patients with liposarcoma or leiomyosarcoma and those without, or between patients with TRS and those without. The most common grade 3-4 AEs were elevated transaminases and neutropenia. CONCLUSION: Trabectedin 1.2 mg/m2, as the approved dose in Japan, showed similar efficacy to the dose of 1.5 mg/m2 used in Western countries. Trabectedin could be an option for advanced STS in Japan, regardless of histological subtype.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Sarcoma/tratamento farmacológico , Trabectedina/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Biomarcadores Tumorais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Sarcoma/diagnóstico , Sarcoma/etiologia , Sarcoma/mortalidade , Trabectedina/administração & dosagem , Trabectedina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
20.
Future Oncol ; 15(26s): 11-15, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31500445

RESUMO

Although 40% of cases of soft tissue sarcoma (STS) are diagnosed in patients aged ≥65 years, this group is largely excluded from or under-represented in clinical trials and receives disproportionately less treatment than younger patients. Pooled analyses and subgroup analyses of Phase II and III randomized controlled trials of systemic therapy in advanced STS suggest the need to revisit this treatment paradigm. In various analyses, efficacy outcomes in older patients did not differ from those in younger patients or in the overall population. Available evidence supports treating elderly STS patients with similar treatment as that for younger patients. However, as some treatments are less well tolerated in older patients, safety must be considered when selecting treatment. As physiological rather than chronological age is a more appropriate criterion for treatment selection, geriatric assessment has a central role in trial design and routine clinical practice. The majority of evidence for the efficacy and safety of systemic therapy in elderly, advanced STS patients has been generated with trabectedin, which is the only agent approved for first-line use in patients unsuited to receive doxorubicin-based regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Fatores Etários , Idoso , Ensaios Clínicos como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Avaliação Geriátrica , Humanos , Ifosfamida/administração & dosagem , Masculino , Prognóstico , Sarcoma/patologia , Taxa de Sobrevida , Trabectedina/administração & dosagem , Gencitabina
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