RESUMEN
Background: GSK3326595 is a potent, selective, reversible protein arginine methyltransferase 5 (PRMT5) inhibitor under investigation for treatment of myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). In preclinical models of AML, PRMT5 inhibition decreased proliferation and increased cell death, supporting additional clinical research in myeloid neoplasms. Objectives: To determine the clinical activity, safety, tolerability, dosing, additional measures of clinical activity, pharmacokinetics, and pharmacodynamics of GSK3326595. Design: In part 1 of this open-label, multicenter, multipart, phase I/II study, adults with relapsed/refractory myeloid neoplasms (e.g., MDS, CMML, and AML) received monotherapy with 400 or 300 mg oral GSK3326595 once daily. Study termination occurred prior to part 2 enrollment. Methods: Clinical activity was determined by the clinical benefit rate (CBR; proportion of patients achieving complete remission (CR), complete marrow remission (mCR), partial remission, stable disease (SD) >8 weeks, or hematologic improvement). Adverse events (AEs) were assessed by incidence and severity. Exploratory examination of spliceosome mutations was performed to determine the relationship between genomic profiles and clinical response to GSK3326595. Results: Thirty patients with a median age of 73.5 years (range, 47-90) were enrolled; 13 (43%) and 17 (57%) received 400 and 300 mg of GSK3326595, respectively. Five (17%) patients met CBR criteria: 4 (13%) with SD >8 weeks and 1 (3%) achieving mCR. Of five patients with clinical benefit: three had SRSF2 mutation, one U2AF1, and one was splicing factor wild-type. Frequent GSK3326595-related AEs were decreased platelet count (27%), dysgeusia (23%), fatigue (20%), and nausea (20%). GSK3326595 had rapid absorption, with a T max of approximately 2 h and a terminal half-life of 4-6 h. Conclusion: GSK3326595 monotherapy had limited clinical activity in heavily pretreated patients despite robust target engagement. The safety profile was broadly consistent with other published PRMT5 inhibitor studies. Trial registration: ClinicalTrials.gov: NCT03614728.
A clinical study to determine the effectiveness and safety of a medication called GSK3326595 in patients with cancers that affect the blood and bone marrow What is this study about? This summary provides the results of a study performed to see how safe and effective treatment with a once daily, oral medication called GSK3326595 was in patients with blood and bone marrow cancers. What are PRMT5 inhibitors? GSK3326595 belongs to a class of medications known as PRMT5 inhibitors. PRMT5 is an enzyme that is involved in many processes in cells. In cancers, too much PRMT5 activity can cause excessive cell growth. This study was performed to see if blocking of PRMT5 by GSK3326595 would help treat patients with blood and bone marrow cancers. What patients were in this study? The patients included in this study had previously received many other cancer treatments. Most patients with these types of cancers have few treatment options and usually pass away due to their disease. What were the results? Five of the 30 patients (17%) included in the study had a response to treatment, including 4 patients with stable disease for more than 8 weeks and 1 patient with complete marrow remission for approximately 8 months. Of the 93% of patients that completed the study, 83% died. Ultimately, all 30 patients discontinued study treatment, mostly due to progression of their disease. The most frequent side effects related to GSK3326595 treatment that occurred in ⩾20% of patients were a decrease in the number of cells that help the blood clot, change in taste bud sense, fatigue, and nausea. The side effects caused by GSK3326595 were similar to what is seen with other PRMT5 inhibitors. Treatment with GSK3326595 provided limited benefits in this patient population and no future studies are planned for GSK3326595 at this time. Additional studies are needed for PRMT5 inhibitors, including combination therapies, to determine which patients with blood and bone marrow cancers could potentially benefit from treatment.
RESUMEN
OBJECTIVE: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. METHODS: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment). RESULTS: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores. CONCLUSIONS: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.
Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inducido químicamente , Calidad de Vida , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Indazoles/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
BACKGROUND: GSK3368715, a first-in-class, reversible inhibitor of type I protein methyltransferases (PRMTs) demonstrated anticancer activity in preclinical studies. This Phase 1 study (NCT03666988) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced-stage solid tumors. METHODS: In part 1, escalating doses of oral once-daily GSK3368715 (50, 100, and 200 mg) were evaluated. Enrollment was paused at 200 mg following a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants, resuming under a protocol amendment starting at 100 mg. Part 2 (to evaluate preliminary efficacy) was not initiated. RESULTS: Dose-limiting toxicities were reported in 3/12 (25%) patients at 200 mg. Nine of 31 (29%) patients across dose groups experienced 12 TEEs (8 grade 3 events and 1 grade 5 pulmonary embolism). Best response achieved was stable disease, occurring in 9/31 (29%) patients. Following single and repeat dosing, GSK3368715 maximum plasma concentration was reached within 1 h post dosing. Target engagement was observed in the blood, but was modest and variable in tumor biopsies at 100 mg. CONCLUSION: Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination. TRIAL REGISTRATION NUMBER: NCT03666988.
Asunto(s)
Antineoplásicos , Neoplasias , Adulto , Humanos , Antineoplásicos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Dosis Máxima Tolerada , Neoplasias/patología , Resultado del TratamientoRESUMEN
Iron overload disorders are characterized by the body's inability to regulate iron absorption and its storage which can lead to organ failures. Accumulated evidence has revealed that hepcidin, the master regulator of iron homeostasis, is negatively modulated by TMPRSS6 (matriptase-2), a liver-specific type II transmembrane serine protease (TTSP). Here, we report that treatment with a peptidomimetic inhibitor affecting TMPRSS6 activity increases hepcidin production in hepatic cells. Moreover, similar effects were observed when using non-peptidic inhibitors obtained through optimization of hits from high-throughput screening. Using HepG2 cells and human primary hepatocytes, we show that TMPRSS6 inhibitors block TMPRSS6-dependent hemojuvelin cleavage and increase HAMP expression and levels of secreted hepcidin.
Asunto(s)
Evaluación Preclínica de Medicamentos , Hepcidinas/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/química , Benzotiazoles/química , Sitios de Unión , Dominio Catalítico , Supervivencia Celular/efectos de los fármacos , Proteínas Ligadas a GPI/metabolismo , Proteína de la Hemocromatosis/metabolismo , Células Hep G2 , Hepatocitos/citología , Hepatocitos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Hierro/metabolismo , Proteínas de la Membrana/metabolismo , Simulación de Dinámica Molecular , Peptidomiméticos , Proteolisis/efectos de los fármacos , Serina Endopeptidasas/química , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Dyslexia is a learning disability characterized by difficulty learning to read and write. The underlying biological and genetic etiology remains poorly understood. One candidate gene, dyslexia susceptibility 1 candidate 1 (DYX1C1), has been shown to be associated with deficits in short-term memory in dyslexic populations. The purpose of the current study was to examine the behavioral phenotype of a mouse model with a homozygous conditional (forebrain) knockout of the rodent homolog Dyx1c1. Twelve Dyx1c1 conditional homozygous knockouts, 7 Dyx1c1 conditional heterozygous knockouts and 6 wild-type controls were behaviorally assessed. Mice with the homozygous Dyx1c1 knockout showed deficits on memory and learning, but not on auditory or motor tasks. These findings affirm existing evidence that DYX1C1 may play an underlying role in the development of neural systems important to learning and memory, and disruption of this function could contribute to the learning deficits seen in individuals with dyslexia.
Asunto(s)
Dislexia/genética , Predisposición Genética a la Enfermedad , Aprendizaje/fisiología , Trastornos de la Memoria/genética , Mutación , Proteínas del Tejido Nervioso/genética , Animales , Modelos Animales de Enfermedad , Genotipo , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , LecturaRESUMEN
DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2-4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).