RESUMO
BACKGROUND: Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. METHODS: This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. RESULTS: Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%). CONCLUSION: Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).
Assuntos
Alcaloides/administração & dosagem , Colangiocarcinoma/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcaloides/efeitos adversos , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
Proteus syndrome (PS) is an ultra-rare disease characterized by progressive, disproportionate, segmental overgrowth caused by a somatic gain-of-function mutation p.Glu17Lys in the oncogene AKT1. The disease has high morbidity and mortality rates due to the increased risk for patients to develop cancer and progressive overgrowth. A teenage patient with severe PS phenotype developed a pelvic recurrence of low-grade serous ovarian carcinoma (LGSOC). Taking into consideration, recent results of the use of AKT inhibitors both in PS and AKT-mutant cancers, we treated the patient on a compassionate basis, with miransertib (ARQ 092), a potent, selective, allosteric AKT inhibitor. Targeted deep sequencing assay of PI3K/AKT pathway genes of the affected overgrowth lesion (cerebriform connective tissue nevus) and the tumor tissues detected the same activating AKT1 mutation in both. Treatment with miransertib led to a complete remission of the cancer and a significant improvement in the patients' everyday life. The treatment is still ongoing at 22 months. This is the first report showing the therapeutic effects of an AKT inhibitor on both benign and malignant tissues that harbor the same pathogenic AKT1 mutation. The present article showed that personalized medicine is feasible in ultra-rare diseases.
Assuntos
Aminopiridinas/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Síndrome de Proteu/tratamento farmacológico , Adolescente , Aminopiridinas/farmacologia , Feminino , Humanos , Imidazóis/farmacologia , Mutação , Neoplasias Ovarianas/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome de Proteu/genética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the AKT1 c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones, asymmetric spinal overgrowth with thoracolumbar scoliosis, dilatation of the inferior vena cava, testicular cystadenoma, bilateral knee deformities, macrodactyly, and apparent intellectual disability. Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor initially developed for cancer therapeutics, now being evaluated for the treatment of PS. After baseline evaluation, the patient started unblinded treatment of 10 mg oral miransertib daily (â¼5 mg/m2/day), escalated to 30 mg daily (â¼15 mg/m2/day), and then to 50 mg daily (â¼25 mg/m2/day) after 3 mo of treatment. Adverse events included dry mouth, one episode of gingivostomatitis, and loose, painful dentition due to preexisting periodontal disease, all of which resolved spontaneously. After 11 mo of treatment, the patient reported improved general well-being, increased mobility of the ankle, spine, and hands, a subjective decrease in size of the right facial bone overgrowth, and reduced areas of cerebriform connective tissue nevi on the soles. Whole-body MRI findings were stable without apparent disease progression. We conclude that 1 yr of treatment with miransertib was beneficial in this case.
Assuntos
Aminopiridinas/uso terapêutico , Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome de Proteu/tratamento farmacológico , Alelos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Duração da Terapia , Humanos , Processamento de Imagem Assistida por Computador , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Síndrome de Proteu/diagnóstico , Síndrome de Proteu/etiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Adulto JovemRESUMO
BACKGROUND: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; Pâ¯<â¯0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360â¯mg twice daily) plus erlotinib (150â¯mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted. RESULTS: Ninety-six patients were randomly assigned to ET (nâ¯=â¯51) or to C (nâ¯=â¯45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; Pâ¯=â¯0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; Pâ¯=â¯0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm. CONCLUSION: In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Docetaxel/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias , Pemetrexede/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: To demonstrate a new interactive Internet-ready database for prospective clinical trials in high-dose-rate (HDR) brachytherapy for prostate cancer. METHODS AND MATERIALS: An Internet-ready database was created that allows common data acquisition and statistical analysis. Patient anonymity and confidentiality are preserved. These data forms include all common elements found from a survey of the databases. The forms allow the user to view patient data in a view-only or edit mode. Eight linked forms document patient data before and after receiving HDR therapy. The pretreatment forms are divided into four categories: staging, comorbid diseases, external beam radiotherapy data, and signs and symptoms. The posttreatment forms separate data by HDR implant information, HDR medications, posttreatment signs and symptoms, and follow-up data. The forms were tested for clinical usefulness. CONCLUSION: This Internet-based database enables the user to record and later analyze all relevant medical data and may become a reliable instrument for the follow-up of patients and evaluation of treatment results.
Assuntos
Adenocarcinoma/radioterapia , Braquiterapia , Bases de Dados Factuais , Internet , Neoplasias da Próstata/radioterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Masculino , Prontuários Médicos , Estudos Prospectivos , Software , Interface Usuário-ComputadorRESUMO
PURPOSE: This work presents a quantitative dosimetric analysis of the Novoste (90)Sr/(90)Y beta-source cardiovascular brachytherapy treatments using a manual pullback technique for patients with in-stent restenosis. METHODS AND MATERIALS: Based on our previous measurements, a model was developed to estimate the dose in the middle of the junction region for tandem irradiation expressed as fraction of prescription dose (FPD) and dosimetric overlap length (DOL) receiving more/less than a threshold dose. The overlap/gap size was measured using the digital cine images recorded during treatment and then FPD and DOL were quantified. RESULTS: Statistical analysis of 55 patients showed that the overlap size and the FPD at 2 mm radial distance were in range of 0 to 23 mm and 13-200% of prescription dose (Rx), respectively. Four gaps out of 76 pullback cases were found, but their size was at most 5 mm. CONCLUSION: Use of a 5 mm overlap avoided underdosed regions in the vast majority of the cases. These results are the first step towards an analysis of the clinical outcome of these patients.
Assuntos
Braquiterapia/instrumentação , Oclusão de Enxerto Vascular/radioterapia , Radioisótopos de Irídio/uso terapêutico , Radiometria/métodos , Radioisótopos de Estrôncio/uso terapêutico , Ponte de Artéria Coronária , Estenose Coronária/cirurgia , Fracionamento da Dose de Radiação , Oclusão de Enxerto Vascular/diagnóstico por imagem , Humanos , Radiografia , Radioterapia Assistida por Computador , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Reported is an analysis of overall survival at 10 years of 102 patients with advanced squamous cell carcinoma of the head and neck (SCCHN) who were enrolled in a prospective phase II trial of high-dose cisplatin, 5-fluorouracil (5-FU), and high-dose leucovorin (PFL) induction chemotherapy followed by surgery and/or definitive radiation therapy (RT) between 1987 and 1991. Initially, 14 patients underwent primary site (PS) and neck surgery irrespective of the clinical response to PFL. The high rate of clinical and pathologic complete response (CR) to PFL prompted a switch from PS surgery to definitive RT. Of 102 patients, 18 (17.6%) who completed PFL and local-regional treatment for SCCHN between 1988 to 1991 were alive in December 2000. Among these, 1 of 14 patients (7%) who had undergone PS resection and 17 of 85 (20%) who were treated after PFL with definitive RT but without PS surgery were alive at 10 years. Median survival time was higher in the nonsurgical group (98.9 vs. 51.9 months). Subset analysis suggested that patients with oropharyngeal PS had the longest median survival (108.6 months). The oropharyngeal patients represented the 61% (11/18) of the long-term survivors with organ preservation. An organ preservation approach for patients with advanced SCCHN who demonstrated PS CR to chemotherapy demonstrated a trend to improved overall survival.