RESUMO
A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity. Fifty-four patients received GSK1795091 with a combination partner; 32 received only the modified GSK1795091 formulation, 15 received only the original formulation, and seven switched mid-study from the original to the modified formulation. Despite the modified formulation demonstrating higher systemic GSK1795091 exposure compared with the original formulation, the transient, dose-dependent elevations in cytokine and chemokine concentrations were no longer observed (e.g., IP-10, IL10, IL1-RA). Most patients (51/54; 94%) experienced ≥1 treatment-emergent adverse event (TEAE) during the study. Safety profiles were similar between formulations, but a higher incidence of TEAEs associated with immune responses (chills, fatigue, pyrexia, nausea, and vomiting) were observed with the original formulation. No conclusions can be made regarding GSK1795091 anti-tumor activity due to the limited data collected. Manufacturing changes were hypothesized to have caused the change in biological activity in this study. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Citocinas , Lipídeo A/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor 4 Toll-Like/agonistas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers. PATIENTS AND METHODS: This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen. RESULTS: Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response. CONCLUSIONS: The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
Assuntos
Antineoplásicos/administração & dosagem , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Indóis/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piridonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Segurança do Paciente , Prognóstico , Piridonas/efeitos adversos , Piridonas/farmacocinética , Distribuição Tecidual , Adulto JovemRESUMO
BACKGROUND: American Indian/Alaska Natives (AI/ANs) are disproportionately affected by hepatitis C virus (HCV), with more than double the national rate of HCV-related mortality as well as the highest rates of acute HCV. The "cascade of care" for HCV consists of screening, confirmation, treatment, and sustained virologic clearance (SVR)/cure. At each stage of this process, patients can be lost to follow-up. Federal health care facilities in an administrative area of the Indian Health Service conducted a review to identify and address gaps in HCV treatment. Facilities generally treated HCV with a strong pharmacy component using a collaborative practice agreement and HCV telehealth services to external specialists. METHODS: All facilities had a pharmacist HCV program point of contact. Each pharmacist conducted a chart review of HCV patients and submitted aggregate results on HCV antibody status, HCV confirmation testing, stage of liver disease, initiation of treatment, and SVR/cure. Each facility also ranked current barriers to scaling up HCV treatment services from a defined list of options. RESULTS: Of 1789 HCV antibody positive patients, 77% (1381) had a confirmation test, of which 67% (929) were positive. Of these patients, 62% (576) had their liver fibrosis scored, and 58% (335) had initiated treatment. Of patients with an SVR/cure test, all (274/274) were negative. DISCUSSION: These data indicate that rural clinics can be successful providing HCV diagnosis and treatment. Pharmacists can play a key role in HCV clinical services. The outcomes of each step in the treatment process at the facility level can vary widely due to local factors. The barriers to HCV care that persist are nonclinical.
Assuntos
Antivirais/administração & dosagem , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Farmacêuticos/organização & administração , United States Indian Health Service/organização & administração , Antivirais/uso terapêutico , Comportamento Cooperativo , Acessibilidade aos Serviços de Saúde/organização & administração , Hepatite C/patologia , Humanos , Indígenas Norte-Americanos , Oklahoma , Papel Profissional , Serviços de Saúde Rural/organização & administração , Índice de Gravidade de Doença , Telemedicina/organização & administração , Estados UnidosRESUMO
PURPOSE: Tumor-derived circulating cell-free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome. EXPERIMENTAL DESIGN: Patients with BRAF V600 mutation-positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined. RESULTS: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K-positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation-positive cfDNA in plasma had higher response rates to dabrafenib and trametinib. CONCLUSIONS: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation-positive tumors. The lack of circulating, BRAF mutation-positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome.