RESUMO
PURPOSE: Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC. PATIENTS AND METHODS: Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2-6, 9-13, and 16-20 of each 21-day cycle. Pretreatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. RESULTS: Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiologic responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and γH2AX, as well as induction of replication fork instability. CONCLUSIONS: No evidence of clinical activity was observed for combined low-dose gemcitabine and LY2880070 in this treatment-refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients.
Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Quinase 1 do Ponto de Checagem , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Estudos de Coortes , Desoxicitidina , Gencitabina , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
CONTEXT: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. OBJECTIVE: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. METHODS: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI)â ≥â 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. RESULTS: Treatment resulted in statistically significant differences compared to placebo in plasma AG (Pâ =â .0002), UAG (Pâ =â .0488), and AG/UAG (Pâ =â .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. CONCLUSION: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.
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Síndrome de Prader-Willi , Aciltransferases , Estudos Cross-Over , Método Duplo-Cego , Grelina/uso terapêutico , Humanos , Hiperfagia , Síndrome de Prader-Willi/tratamento farmacológicoRESUMO
Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0-1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934 .
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Aurora Quinase A/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity. METHODS: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3). PRCL-02 was administered via a surgically inserted gastrostomy tube BID. RESULTS: Dose-related drug exposure in monkeys was established and renal transplants were then performed using PRCL-02 monotherapy. Oral dosing of PRCL-02 was well tolerated and resulted in suppressed T-cell proliferation in in vitro MLR comparable to animals in the tacrolimus control arm. Animals receiving tacrolimus monotherapy were e on day 100 without rejection. PRCL-02 monotherapy only marginally prolonged graft survival (MST = 13.16 d; group 2) compared with untreated controls. Animals treated initially with tacrolimus and converted to PRCL-02 monotherapy had a mean graft survival of 35.3 days which was prolonged compared with PRCL-02 monotherapy but not compared with the tacrolimus-treated group. Pharmacokinetic studies showed inconsistent drug exposures despite attempts to adjust dose and exposure which may have contributed to the rejections. CONCLUSIONS: We conclude that, in this nonhuman primate model of kidney transplantation, PRCL-02 demonstrated evidence of in vivo immunosuppressive activity but was inferior to tacrolimus treatment with respect to suppressing immune transplant rejection.
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Canais de Cálcio Ativados pela Liberação de Cálcio/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Terapia de Imunossupressão/métodos , Transplante de Rim , Tacrolimo/uso terapêutico , Animais , Inibidores de Calcineurina/uso terapêutico , Modelos Animais de Doenças , Rejeição de Enxerto/diagnóstico , Macaca mulatta , Masculino , Transplante Homólogo , Resultado do TratamentoRESUMO
Continuous glucose monitoring (CGM) systems allow patients with diabetes mellitus to closely track glucose concentrations over several days, identify trends in glucose levels, and avoid glucose excursions. This technology has not only advanced diabetes mellitus management but has increased patient safety through greater glycemic awareness. Due to these attributes, CGM is now being applied in therapeutic research as a pharmacodynamic tool to support early clinical drug development programs. However, to date only a handful of studies have utilized CGM in type 2 diabetes mellitus (T2DM) drug development. A potential barrier from fostering greater use of CGM in clinical development may be related to concerns over subject variability. Therefore, we investigated a key consideration when implementing CGM into early clinical research studies: daily variation within patients with T2DM from multiple clinical research units. From 24 patients with T2DM, we observed strong daily reproducibility (Pearson R = 0.86, P < .0001) in CGM results and found that this technique is practical for multisite studies. Altogether, with low daily variability, CGM is a powerful pharmacodynamic tool for drug efficacy and safety monitoring.