RESUMO
Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Inibidores de Histona Desacetilases/efeitos adversos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/etiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors. METHODS: Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%. RESULTS: Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls. CONCLUSION: Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).
Assuntos
Anemia , Neoplasias Pulmonares , Neutropenia , Carcinoma de Pequenas Células do Pulmão , Trombocitopenia , Humanos , Masculino , Feminino , Etoposídeo , Carboplatina , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Teorema de Bayes , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamente , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Navtemadlin is an orally bioavailable small molecule that blocks the protein-protein interaction between murine double minute 2 protein (MDM2) and the tumor suppressor protein p53, leading to p53-mediated cell cycle arrest and apoptosis. It is being evaluated in clinical trials for a variety of malignancies, both as a single agent and in combination regimens. A sensitive, robust LC-tandem mass spectrometry (LC-MS/MS) method was developed to quantitate navtemadlin in plasma, and this method was also validated using brain tissue homogenate. Sample preparation involved protein precipitation of plasma or brain tissue homogenate using acetonitrile. Navtemadlin, navtemadlin glucuronide, and the internal standard, D6 -navtemadlin, were separated from microsomal incubation extracts using gradient elution and a ZORBAX XDB C18 column. Analytes were detected using a SCIEX 5500 triple quadrupole mass spectrometer in positive electrospray ionization mode. The assay range of 1-1000 ng/mL was shown to be accurate (96.1-102.0% and 95.7-104%) and precise (coefficient of variation ≤ 10.6% and ≤ 6.6%) in plasma and brain tissue homogenate, respectively. An 8000 ng/mL navtemadlin sample diluted 1:10 (v/v) with plasma was also accurately quantitated. Navtemadlin has been stable in frozen plasma at -70°C for at least 20 months. This validated LC-MS/MS method was applied to determine navtemadlin concentrations in plasma and brain tissue samples from two separate patients receiving 120 mg/day navtemadlin on protocol ABTC1604.
Assuntos
Espectrometria de Massas em Tandem , Proteína Supressora de Tumor p53 , Acetonitrilas , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Glucuronídeos/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. METHODS: A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab. RESULTS: The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. DISCUSSION: This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/enzimologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Lapatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
AIMS: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
Assuntos
Inibidores de Histona Desacetilases/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Hepatopatias/fisiopatologia , Fígado/metabolismo , Neoplasias/tratamento farmacológico , Sulfonamidas/farmacocinética , Adulto , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Infusões Intravenosas , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/complicações , Neoplasias/patologia , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversosRESUMO
KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Duplicação Gênica , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Sequências de Repetição em Tandem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Resistência a Medicamentos , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva , Retratamento , Adulto JovemRESUMO
The standard-of-care for advanced small cell lung cancer (SCLC) is chemotherapy with cisplatin+etoposide (C+E). Most patients have chemosensitive disease at the outset, but disease frequently relapses and limits survival. Efforts to improve therapeutic outcomes in SCLC and other neuroendocrine cancers have focused on epigenetic agents, including the histone deacetylase inhibitor belinostat. The primary objective was to determine the maximum tolerated dose of the combination of belinostat (B) with C+E. Belinostat was administered as a 48-h continuous intravenous infusion on days 1-2; cisplatin was administered as a 1-h intravenous infusion on day 2; and etoposide was administered as a 1-h intravenous infusion on days 2, 3, and 4. Twenty-eight patients were recruited in this single-center study. The maximum tolerated dose was belinostat 500 mg/m/24 h, cisplatin 60 mg/m, and etoposide 80 mg/m. The combination was safe, although some patients were more susceptible to adverse events. Hematologic toxicities were most commonly observed. Objective responses were observed in 11 (39%) of 28 patients and seven (47%) of 15 patients with neuroendocrine tumors (including SCLC). Patients carrying more than three copies of variant UGT1A1 (*28 and *60) had higher serum levels of belinostat because of slower clearance. DNA damage peaked at 36 h after the initiation of belinostat, as did global lysine acetylation, but returned to baseline 12 h after the end of infusion. The combination of B+C+E is safe and active in SCLC and other neuroendocrine cancers. Future phase II studies should consider genotyping patients for UGT1A1*28 and UGT1A1*60 and to identify patients at an increased risk of adverse events.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Glucuronosiltransferase/genética , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/sangue , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Infusões Intravenosas , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Sulfonamidas/administração & dosagem , Resultado do TratamentoRESUMO
OBJECTIVE: This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS). METHODS: Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age≥18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing a tumor response to less than or equal to 5% and the probability of a patient surviving event-free for at least 6months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts. cumulative for stage 2. Confidence intervals do not correct for multiplicity. RESULTS: Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia Hensley et al. (2008a) , leukopenia Hensley et al. (2008b) , neutropenia Maki et al. (2007) , thrombocytopenia Huang et al. (2012) , mucositis Hensley et al. (2008a) , diarrhea Huang et al. (2012) , and palmer-planter syndrome Zivanovic et al. (2012) . There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.6 - NA), respectively. CONCLUSION: Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS.
Assuntos
Antineoplásicos/uso terapêutico , Azepinas/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Azepinas/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Taxa de SobrevidaRESUMO
AIMS: Veliparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzyme. The objectives of the analysis were to evaluate the effect of baseline covariates and co-administration of topotecan plus carboplatin (T + C) on pharmacokinetics of veliparib in patients with refractory acute leukaemia, and compare veliparib concentration in various biological matrices. METHODS: A population pharmacokinetic model was developed and effect of age, body size indices, sex, creatinine clearance (CrCL) and co-administration of T + C on the pharmacokinetics of veliparib were evaluated. The final model was qualified using bootstrap and quantitative predictive check. Linear regression was conducted to correlate concentrations of veliparib in various biological matrices. RESULTS: A two compartment model with first-order absorption with Tlag described veliparib pharmacokinetics. The apparent clearance (CL/F) and volume (Vc /F) were 16.5 l h-1 and 122.7 l, respectively. The concomitant administration of T + C was not found to affect veliparib CL/F. CrCL and lean body mass (LBM) were significant covariates on CL/F and Vc/F, respectively. While a strong positive relationship was observed between veliparib concentrations in plasma and bone marrow supernatant, no correlation was observed between plasma and peripheral blood or bone marrow blasts. CONCLUSIONS: Consistent with veliparib's physiochemical properties and its elimination mechanism, LBM and CrCL were found to affect pharmacokinetics of veliparib while concomitant administration of T + C did not affect veliparib's CL/F. Plasma concentrations were found to be a reasonable surrogate for veliparib concentrations in peripheral blood and bone marrow supernatant but not blasts. The current model will be utilized to conduct exposure-response analysis to support dosing recommendations.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzimidazóis/farmacocinética , Leucemia/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/análise , Benzimidazóis/uso terapêutico , Carboplatina/farmacocinética , Carboplatina/uso terapêutico , Cálculos da Dosagem de Medicamento , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Leucemia/sangue , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Biológicos , Inibidores de Poli(ADP-Ribose) Polimerases/análise , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Topotecan/farmacocinética , Topotecan/uso terapêutico , Adulto JovemRESUMO
Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer. An ECOG-ACRIN Phase III registration study is ongoing in advanced breast cancer (E2112, NCT02115282) and aims to confirm the overall survival advantage observed with the combination of exemestane and entinostat/placebo in the Phase II setting (ENCORE301 trial). This article provides an overview of the chemistry, pharmacokinetics/pharmacodynamics and available clinical data for entinostat with a focus on advanced breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Inibidores de Histona Desacetilases/administração & dosagem , Piridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Apoptose/efeitos dos fármacos , Benzamidas/efeitos adversos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Epigênese Genética/genética , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Estadiamento de Neoplasias , Piridinas/efeitos adversosRESUMO
AIMS: The US National Cancer Institute recently developed the PRO-CTCAE (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events). PRO-CTCAE is a library of questions for clinical trial participants to self-report symptomatic adverse events (e.g. nausea). The objective of this study is to inform evidence-based selection of a recall period when PRO-CTCAE is included in a trial. We evaluated differences between 1-, 2-, 3-, and 4-week recall periods, using daily reporting as the reference. METHODS: English-speaking patients with cancer receiving chemotherapy and/or radiotherapy were enrolled at four US cancer centers and affiliated community clinics. Participants completed 27 PRO-CTCAE items electronically daily for 28 days, and then weekly over 4 weeks, using 1-, 2-, 3-, and 4-week recall periods. For each recall period, mean differences, effect sizes, and intraclass correlation coefficients were calculated to evaluate agreement between the maximum of daily ratings and the corresponding ratings obtained using longer recall periods (e.g. maximum of daily scores over 7 days vs 1-week recall). Analyses were repeated using the average of daily scores within each recall period rather than the maximum of daily scores. RESULTS: A total of 127 subjects completed questionnaires (57% male; median age: 57). The median of the 27 mean differences in scores on the PRO-CTCAE 5-point response scale comparing the maximum daily versus the longer recall period (and corresponding effect size) was -0.20 (-0.20) for 1-week recall, -0.36 (-0.31) for 2-week recall, -0.45 (-0.39) for 3-week recall, and -0.47 (-0.40) for 4-week recall. The median intraclass correlation across 27 items between the maximum of daily ratings and the corresponding longer recall ratings for 1-week recall was 0.70 (range: 0.54-0.82), for 2-week recall was 0.74 (range: 0.58-0.83), for 3-week recall was 0.72 (range: 0.61-0.84), and for 4-week recall was 0.72 (range: 0.64-0.86). Similar results were observed for all analyses using the average of daily scores rather than the maximum of daily scores. CONCLUSION: A 1-week recall corresponds best to daily reporting. Although intraclass correlations remain stable over time, there are small but progressively larger differences between daily and longer recall periods at 2, 3, and 4 weeks, respectively. The preferred recall period for the PRO-CTCAE is the past 7 days, although investigators may opt for recall periods of 2, 3, or 4 weeks with an understanding that there may be some information loss.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/classificação , Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Neoplasias , Medidas de Resultados Relatados pelo Paciente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Idoso , Quimiorradioterapia/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Rememoração Mental , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Autorrelato , Fatores de Tempo , Estados Unidos , Adulto JovemRESUMO
Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Depsipeptídeos/efeitos adversos , Epigenômica , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Cutâneas/patologiaRESUMO
To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Reguladoras de Apoptose/genética , Depsipeptídeos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas de Membrana/genética , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Ensaios Clínicos Fase II como Assunto , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas/metabolismo , Racionalização , Transcriptoma , Células Tumorais CultivadasRESUMO
We have developed and validated a novel LC-MS/MS method for the simultaneous quantification of ZEN-3694 and its active metabolite ZEN-3791 in human plasma after protein precipitation. Stable isotope-labeled versions were used as internal standards. Chromatographic separation was achieved on a Kinetex C18 column using 0.1% formic acid in H2O and 0.1% formic acid in MeOH as mobile phases. Detection was performed via positive electrospray ionization mode with multiple reaction monitoring. The assay exhibited linearity in the concentration range of 5-5000 ng/ml for both analytes. Intra- and inter-assay precision and accuracy were within ±11%. ZEN-3694 and ZEN-3791 recoveries were between 93 and 105%. This LC-MS/MS assay is an essential tool to study ZEN-3694 in an ongoing clinical trial (NCT04840589).
[Box: see text].
Assuntos
Espectrometria de Massa com Cromatografia Líquida , Humanos , Espectrometria de Massa com Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
Belinostat was approved in 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma, however, there was insufficient data to recommend a dose in patients with moderate to severe hepatic impairment. The purpose of this analysis was to characterize the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers and varying degrees of liver dysfunction. A population pharmacokinetic model was therefore developed to describe the parent-metabolite system. The final model was then implemented to assess the effect of liver impairment on each metabolic pathway of belinostat. It was determined that significant pharmacokinetic differences could only be demonstrated in patients with severe hepatic impairment. The final model estimated a 35%-47% reduction in metabolic clearance attributed to UGT1A1/2B7 glucuronidation, CYP2A6/3A4/2C9 metabolism, and ß-oxidation. These hepatic impairment effects reduced between-subject variability by only 5%-8% for their respective parameter, with a large amount of remaining unexplained variability. With further validation, this model can be leveraged to assess the need for dose adjustments in this patient population.
Assuntos
Ácidos Hidroxâmicos , Neoplasias , Sulfonamidas , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Sulfonamidas/farmacocinética , Sulfonamidas/administração & dosagem , Masculino , Modelos Biológicos , Feminino , Pessoa de Meia-Idade , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Hepatopatias/metabolismo , Idoso , Adulto , Taxa de Depuração MetabólicaRESUMO
We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Ipilimumab , Nivolumabe , Piridinas , Receptor ErbB-2 , Humanos , Feminino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Adulto , Receptor ErbB-2/metabolismo , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Idoso , Ipilimumab/uso terapêutico , Ipilimumab/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Intervalo Livre de ProgressãoRESUMO
PURPOSE: Amplification of CDK4 and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-MATCH trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors. PATIENTS AND METHODS: Patients had a solid malignancy with progression on at least one systemic therapy for advanced disease. Tumors with ≥ 7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1-21 of a 28-day cycle. The primary endpoint was ORR. RESULTS: Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for ORR endpoint. Among the 25 patients in the primary cohort, one patient had a PR, 4 patients had SD, and 16 patients had PD as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a PR, 10 patients had SD, and 21 patients had PD as best response. Partial response and stable disease were only seen in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months. CONCLUSIONS: Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, though CNS tumors may be worthy of future investigation.
RESUMO
Romidepsin (depsipeptide or FK228) is a histone deacetylase inhibitor, one of a new class of agents active in T-cell lymphoma. A phase 2 trial was conducted in cutaneous (CTCL) and peripheral (PTCL) T-cell lymphoma. Major and durable responses in CTCL supported the approval of romidepsin for CTCL. Forty-seven patients with PTCL of various subtypes including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma were enrolled. All patients had received prior therapy with a median of 3 previous treatments (range 1-11); 18 (38%) had undergone stem-cell transplant. All patients were evaluated for toxicity; 2 patients discovered to be ineligible were excluded from response assessment. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. Complete responses were observed in 8 and partial responses in 9 of 45 patients, for an overall response rate of 38% (95% confidence interval 24%-53%). The median duration of overall response was 8.9 months (range 2-74). Responses were observed in various subtypes, with 6 responses among the 18 patients with prior stem-cell transplant. The histone deacetylase inhibitor romidepsin has single agent clinical activity associated with durable responses in patients with relapsed PTCL.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/farmacocinética , Depsipeptídeos/farmacocinética , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Neoplasias Cutâneas/tratamento farmacológico , Taxa de Sobrevida , Distribuição Tecidual , Resultado do TratamentoRESUMO
BACKGROUND: Rectal carcinomas are tumors that arise from the last 12 cm of the large intestine closest to the anus. They generally have a modest prognosis exacerbated by a high local recurrence rate if radiosensitizing chemotherapy is not given during radiotherapy. This case report discusses the clinical trial treatment of a patient with rectal adenocarcinoma by a new ropidoxuridine-capecitabine-radiotherapy combination. This case report is novel due to the patient's participation in an accelerated titration phase I clinical trial and the resultant rare adverse event of treatment-related sigmoid typhlitis. CASE PRESENTATION: The patient was an 82-year-old female who noticed hematochezia and change in stool caliber over a period of 3 months. A rectal mass was identified by biopsy as a microsatellite stable adenocarcinoma. A planned total neoadjuvant treatment involved eight cycles of leucovorin calcium (folinic acid)-fluorouracil-oxaliplatin (mFOLFOX6) chemotherapy, followed by a clinical trial combination of ropidoxuridine-capecitabine-radiotherapy, prior to definitive surgery. The patient began daily intensity modulated pelvic radiotherapy with concurrent twice-daily oral ropidoxuridine and twice-daily oral capecitabine to be given over 6 weeks. After 14 days of ropidoxuridine-capecitabine-radiotherapy, the patient developed sigmoid typhlitis requiring a 10-day hospitalization and 14-day disruption of treatment. The patient died 27 days after the start of ropidoxuridine-capecitabine-radiotherapy. This adverse event was listed as a definite attribution to the ropidoxuridine-capecitabine treatment; pharmacokinetic and pharmacodynamic data showed low ropidoxuridine metabolite DNA incorporation and high capecitabine metabolite concentration. The accelerated titration phase I clinical trial has been subsequently closed to accrual (NCT04406857). CONCLUSIONS: We believe this case report demonstrates the decision-making process for terminating a phase I accelerated titration designed clinical trial. The report also presents the rare complication of sigmoid typhlitis as a treatment-attributed adverse event. In this case, a ropidoxuridine-capecitabine combination was used as an investigational radiosensitizing treatment now with a narrower future clinical development pathway.