RESUMO
BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.
Assuntos
Vaga-Lumes , Glioma , Animais , Criança , Humanos , Adulto Jovem , Vaga-Lumes/metabolismo , Proteínas Proto-Oncogênicas B-raf , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Resultado do Tratamento , Mutação , Proteínas Quinases Ativadas por Mitógeno , Oximas , Piridonas , Pirimidinonas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .
Assuntos
Vaga-Lumes , Glioma , Humanos , Criança , Animais , Proteínas Proto-Oncogênicas B-raf/genética , Glioma/tratamento farmacológico , Glioma/genéticaRESUMO
BACKGROUND: Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. METHODS: We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321. FINDINGS: We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9-83·7) and confirmed responses in 18 (50%, 32·9-67·1). 21 (78%, 57·7-91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3-74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer. INTERPRETATION: Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. FUNDING: GlaxoSmithKline.
Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Adulto , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma de Células Escamosas/induzido quimicamente , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Febre/induzido quimicamente , Genótipo , Humanos , Imidazóis/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Dose Máxima Tolerável , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/secundário , Pessoa de Meia-Idade , Mutação/genética , Neoplasias/genética , Oximas/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/induzido quimicamente , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , VemurafenibRESUMO
A phase I study was conducted to assess the metabolism and excretion of [(14)C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 µCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-high-performance liquid chromatography--tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy- and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned α to an alkyl (ethyl or t-butyl) side chain.
Assuntos
Carbono/metabolismo , Descarboxilação/fisiologia , Imidazóis/metabolismo , Neoplasias/metabolismo , Nitrogênio/metabolismo , Oximas/metabolismo , Administração Oral , Adulto , Fezes/química , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Adulto JovemRESUMO
We report a case of a mediastinal seminoma occurring 19 months after the resolution of a pineal germinoma. A 15-year-old boy with headaches and visual changes was diagnosed with a pineal germinoma by biopsy and mildly elevated beta-human chorionic gonadatropin (beta-HCG) in serum and cerebral spinal fluid. Radiation therapy leads to the resolution of his pineal germinoma and normalization of the beta-HCG. A mediastinal seminoma (germinoma) was diagnosed nearly 2 years later because of rising serum beta-HCG. There was no evidence of recurrent central nervous system disease. The patient underwent systemic chemotherapy with the complete resolution of the mediastinal seminoma.
Assuntos
Germinoma/radioterapia , Neoplasias do Mediastino/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Pinealoma/radioterapia , Seminoma/tratamento farmacológico , Adolescente , Gonadotropina Coriônica Humana Subunidade beta/sangue , Gonadotropina Coriônica Humana Subunidade beta/líquido cefalorraquidiano , Germinoma/sangue , Germinoma/líquido cefalorraquidiano , Germinoma/patologia , Humanos , Masculino , Neoplasias do Mediastino/sangue , Neoplasias do Mediastino/líquido cefalorraquidiano , Neoplasias do Mediastino/patologia , Segunda Neoplasia Primária/sangue , Segunda Neoplasia Primária/líquido cefalorraquidiano , Segunda Neoplasia Primária/patologia , Pinealoma/sangue , Pinealoma/líquido cefalorraquidiano , Pinealoma/patologia , Seminoma/sangue , Seminoma/líquido cefalorraquidiano , Seminoma/patologia , Fatores de TempoRESUMO
OBJECTIVES: Neuroblastoma is the most common extracranial solid tumor of childhood, and the most common malignancy diagnosed during infancy. In comparison, neonatal neuroblastoma is relatively rare. Improvements in prenatal imaging and widespread use of fetal ultrasonography have led to an increased rate of prenatal diagnoses. METHODS: Case report and literature review. RESULTS: We report a case of an intermediate-risk neuroblastoma, diagnosed at 36 weeks' gestation by ultrasound and subsequently visualized by fetal MRI, that resulted in spinal cord compression and decreased fetal movement. A multidisciplinary team approach resulted in rapid delivery, evaluation, biopsy, staging, and treatment implementation in a successful effort to preserve lower extremity function. CONCLUSION: Prenatal diagnosis of neuroblastoma, management and outcomes are reviewed. Prompt diagnosis can strongly influence perinatal management and improve prognosis.
Assuntos
Doenças Fetais/patologia , Neuroblastoma/patologia , Diagnóstico Pré-Natal , Neoplasias da Coluna Vertebral/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia por Agulha , Parto Obstétrico , Feminino , Movimento Fetal , Idade Gestacional , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Neuroblastoma/complicações , Neuroblastoma/tratamento farmacológico , Neuroblastoma/embriologia , Gravidez , Compressão da Medula Espinal/embriologia , Compressão da Medula Espinal/patologia , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/tratamento farmacológico , Neoplasias da Coluna Vertebral/embriologia , Resultado do Tratamento , Ultrassonografia Pré-NatalAssuntos
Proteínas Proto-Oncogênicas B-raf , Sarcoma , Criança , Humanos , Biomarcadores Tumorais/genética , Fusão Gênica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Proteínas Proto-Oncogênicas B-raf/genética , Sarcoma/tratamento farmacológico , Sarcoma/genética , Nexinas de Classificação/genéticaRESUMO
The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.
Assuntos
Genfibrozila/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Cetoconazol/farmacologia , Oximas/administração & dosagem , Oximas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Anticoagulantes/farmacocinética , Inibidores do Citocromo P-450 CYP2C8/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Feminino , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Oximas/metabolismo , Oximas/farmacologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Varfarina/farmacocinéticaRESUMO
PURPOSE: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship. EXPERIMENTAL DESIGN: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data. RESULTS: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma. CONCLUSION: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.
Assuntos
Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Oximas/efeitos adversos , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Resultado do TratamentoRESUMO
Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild-type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single-center, open-label study in four patients with BRAF mutation-positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median T(max) after oral administration was 2.0 hours and the geometric mean terminal half-life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first-pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer.
Assuntos
Imidazóis/farmacocinética , Neoplasias/metabolismo , Oximas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Disponibilidade Biológica , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/sangue , Masculino , Mutação , Oximas/administração & dosagem , Oximas/sangue , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Dabrafenib is a small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF V600 mutation-positive melanoma. This clinical, open-label, two-cohort (n = 14 per cohort), randomized study was designed to evaluate the effect of drug substance particle size, and food on the plasma pharmacokinetics of a single oral dose of dabrafenib in patients with BRAF V600 mutation-positive solid tumors. In addition, an exploratory cross-cohort comparison of the relative bioavailability of single-dose dabrafenib administered in gelatin and hydroxypropyl methylcellulose (HPMC) capsules was performed. Higher bioavailability was noted with nonmicronized drug substance (larger particle size), under fasting conditions, and with HPMC capsules. Initial dissolution results at pH 1.2 showed higher dissolution of gelatin relative to HPMC capsules inconsistent with clinical data. Subsequent in vitro dissolution studies were conducted in fasted-state simulated gastric fluid over a 24-h period and showed that HPMC capsules reached a higher percentage of dabrafenib dissolved than gelatin capsules. The presence of HPMC is believed to inhibit precipitation of dabrafenib as the freebase, thereby maintaining a supersaturated solution over an extended period of time. Dabrafenib has been administered in pivotal clinical studies on an empty stomach using micronized drug substance in HPMC capsules.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Imidazóis/administração & dosagem , Imidazóis/sangue , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Oximas/sangue , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Cápsulas/química , Estudos de Coortes , Jejum , Feminino , Humanos , Derivados da Hipromelose , Masculino , Melanoma/genética , Metilcelulose/análogos & derivados , Metilcelulose/química , Pessoa de Meia-Idade , Tamanho da Partícula , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
The authors describe a patient with autosomal-recessive severe combined immunodeficiency (SCID) with severe, multiorgan cytomegalovirus (CMV) disease. In the face of appropriate therapy, the patient developed a 100-fold gradient in viral load across the blood-brain barrier. Disseminated disease, including pneumonitis, contributed to a fatal outcome. Serial genotypic analyses revealed multiple UL97 and UL54 (DNA polymerase) mutations that conferred phenotypic resistance to all currently licensed systemic CMV antivirals.