RESUMEN
PURPOSE: Abiraterone acetate, prescribed for metastatic prostate cancer, has enhanced absorption with food. This effect was exploited in a randomized trial which showed noninferiority of PSA decline for 250 mg abiraterone with a low-fat meal (LOW) compared to 1,000 mg abiraterone fasting (STD). Drug was obtained via patient insurance. Patient out-of-pocket costs and adherence were surveyed. METHODS: Trial participants were randomized to STD or LOW, and surveys of adherence and out-of-pocket costs were administered at baseline and just before coming off study (follow-up). RESULTS: Out-of-pocket costs were available from 20 of 36 STD and 21 of 36 LOW patients. Median out-of-pocket costs for a month of drug were $0 (LOW) and $5 (STD); mean costs were $43.61 (LOW) and $393.83 (STD). The two groups did not differ significantly (p = 0.421). Maximum out-of-pocket cost was $1,000 (LOW) and $4,000 (STD). Monthly out-of-pocket costs > $500 were found in 1 LOW and 5 STD patients. For adherence, only 11 STD and 19 LOW patients had questionnaires completed at both baseline and follow-up. STD adherence was 98.18% at baseline and 91.69% at follow-up, differing significantly (p = 0.0078). LOW adherence was 96.52% at baseline and 97.86% at follow-up, not differing significantly (p = 0.3511). Adherence did not correlate with demographics. At follow-up, increasing adherence correlated significantly with decreasing dose (p = 0.013; rho = - 0.458). CONCLUSIONS: Out-of-pocket costs did not differ significantly in this limited analysis. Adherence was significantly different in STD as the trial progressed, which was not found in LOW. TRIAL REGISTRATION: ClinicalTrials.gov NCT01543776; registered March 5, 2012.
Asunto(s)
Gastos en Salud , Neoplasias de la Próstata Resistentes a la Castración , Androstenos , Humanos , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Although it is known that trastuzumab causes cardiotoxicity, its extent and reversibility are still in question. Earlier studies have not evaluated consecutive patients with reproducible nuclear ventriculography. OBJECTIVE: We sought to evaluate the baseline characteristics which predispose patients to increased risk of trastuzumab cardiotoxicity and to determine the natural history of the cardiotoxicity. METHODS AND RESULTS: Left ventricular ejection fraction (LVEF) was measured in 76 women aged 36-73 years who had been treated with trastuzumab at the University of Maryland Greenebaum Cancer Center. LVEF was determined at baseline and then 3, 6, 9, and 12 months after treatment initiation. Cardiotoxicity was defined as ≥ 16% decrease in LVEF or ≥ 10% decrease in LVEF to <50%. There were no differences in comorbidities, earlier treatment, or demographics between patients with and without trastuzumab-induced cardiomyopathy except that African Americans were more likely to develop decreased LVEF (P < .05). Twenty-one patients (28%) met criteria for cardiotoxicity. Four of those patients were continued on trastuzumab and 17 patients had therapy withheld at some point. Only 1 patient developed symptomatic heart failure requiring inpatient hospitalization. LVEF improved in most patients regardless of whether or not trastuzumab was continued. CONCLUSIONS: Decreased LVEF while undergoing trastuzumab therapy occurs frequently and is usually reversible. African Americans had a higher risk of developing decreased LVEF. These findings raise clinically important questions as to whether it is necessary to discontinue trastuzumab for asymptomatic decrease in LVEF and whether African Americans are more predisposed to a decrease in LVEF while receiving trastuzumab. Further studies carefully assessing LVEF should address these hypotheses.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Cardiomiopatías/inducido químicamente , Medición de Riesgo/métodos , Población Urbana , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Cardiomiopatías/epidemiología , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Maryland/epidemiología , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , TrastuzumabRESUMEN
PURPOSE: We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene. PATIENTS AND METHODS: We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model. RESULTS: In ATMm (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8). CONCLUSION: In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.
Asunto(s)
Proteína BRCA2 , Mutación , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Próstata Resistentes a la Castración , Ensayos Clínicos Controlados Aleatorios como Asunto , Reparación del ADN por Recombinación , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Masculino , Reparación del ADN por Recombinación/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Estados Unidos , Quinasa de Punto de Control 2/genética , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Supervivencia sin Progresión , Antagonistas de Receptores Androgénicos/uso terapéutico , Anciano , Receptores Androgénicos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. RESULTS: A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated (BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. CONCLUSION: Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Aprobación de Drogas , Mutación , Nitrilos , Feniltiohidantoína , Ftalazinas , Neoplasias de la Próstata Resistentes a la Castración , Reparación del ADN por Recombinación , United States Food and Drug Administration , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/análogos & derivados , Benzamidas/uso terapéutico , Estados Unidos , Ftalazinas/uso terapéutico , Ftalazinas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Método Doble Ciego , Persona de Mediana Edad , Anciano de 80 o más Años , Supervivencia sin ProgresiónRESUMEN
Neurotropic flaviviruses can efficiently replicate in the developing and mature central nervous systems (CNS) of mice causing lethal encephalitis. Insertion of a single copy of a target for brain-expressed microRNAs (miRNAs) in the 3' noncoding region (3'NCR) of the flavivirus genome (chimeric tick-borne encephalitis virus/dengue virus) abolished virus neurovirulence in the mature mouse CNS. However, in the developing CNS of highly permissive suckling mice, the miRNA-targeted viruses can revert to a neurovirulent phenotype by accumulating deletions or mutations within the miRNA target sequence. Virus escape from miRNA-mediated suppression in the developing CNS was markedly diminished by increasing the number of miRNA target sites and by extending the distance between these sites in the virus genome. Insertion of multiple miRNA targets into the 3'NCR altered virus neuroinvasiveness, decreased neurovirulence and neuroinflammatory responses, and prevented neurodegeneration without loss of immunogenicity. Although the onset of encephalitis was delayed, a small number of suckling mice still succumbed to lethal intracerebral infection with the miRNA-targeted viruses. Sequence analysis of brain isolates from moribund mice revealed that the viruses escaped from miRNA-mediated suppression exclusively through the deletion of miRNA targets and viral genome sequence located between the two miRNA targets separated by the greatest distance. These findings offer a general strategy to control the reversion of virus to a virulent phenotype: a simultaneous miRNA targeting of the viral genome at many different functionally important regions could prevent virus escape from miRNA-based attenuation, since a deletion of the targeted genomic sequences located between the inserted miRNA binding sites would be lethal for the virus.
Asunto(s)
Enfermedades del Sistema Nervioso Central/virología , Virus del Dengue/genética , Virus del Dengue/patogenicidad , Virus de la Encefalitis Transmitidos por Garrapatas/genética , Virus de la Encefalitis Transmitidos por Garrapatas/patogenicidad , Infecciones por Flavivirus/virología , MicroARNs/genética , Liberación del Virus , Animales , Secuencia de Bases , Virus del Dengue/química , Virus del Dengue/fisiología , Virus de la Encefalitis Transmitidos por Garrapatas/química , Virus de la Encefalitis Transmitidos por Garrapatas/fisiología , Marcación de Gen , Humanos , Ratones , MicroARNs/metabolismo , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Fenotipo , Virulencia , Replicación ViralRESUMEN
Flaviviruses such as West Nile, Japanese encephalitis, and tick-borne encephalitis (TBEV) viruses are important neurotropic human pathogens, causing a devastating and often fatal neuroinfection. Here, we demonstrate that incorporation into the viral genome of a target sequence for cellular microRNAs expressed in the central nervous system (CNS) enables alteration of the neurovirulence of the virus and control of the neuropathogenesis of flavivirus infection. As a model virus for this type of modification, we used a neurovirulent chimeric tick-borne encephalitis/dengue virus (TBEV/DEN4) that contained the structural protein genes of a highly pathogenic TBEV. The inclusion of just a single target copy for a brain tissue-expressed mir-9, mir-124a, mir-128a, mir-218, or let-7c microRNA into the TBEV/DEN4 genome was sufficient to prevent the development of otherwise lethal encephalitis in mice infected intracerebrally with a large dose of virus. Viruses bearing a complementary target for mir-9 or mir-124a were highly restricted in replication in primary neuronal cells, had limited access into the CNS of immunodeficient mice, and retained the ability to induce a strong humoral immune response in monkeys. This work suggests that microRNA targeting to control flavivirus tissue tropism and pathogenesis might represent a rational approach for virus attenuation and vaccine development.
Asunto(s)
Virus del Dengue/patogenicidad , Virus de la Encefalitis Transmitidos por Garrapatas/patogenicidad , MicroARNs/genética , Mutagénesis Insercional , Proteínas Recombinantes de Fusión/genética , Animales , Anticuerpos Antivirales/sangre , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/virología , Células Cultivadas , Chlorocebus aethiops , Culicidae/virología , Dengue/genética , Dengue/inmunología , Dengue/prevención & control , Dengue/virología , Virus del Dengue/genética , Virus del Dengue/crecimiento & desarrollo , Virus del Dengue/inmunología , Virus de la Encefalitis Transmitidos por Garrapatas/genética , Virus de la Encefalitis Transmitidos por Garrapatas/crecimiento & desarrollo , Virus de la Encefalitis Transmitidos por Garrapatas/inmunología , Encefalitis Transmitida por Garrapatas/genética , Encefalitis Transmitida por Garrapatas/inmunología , Encefalitis Transmitida por Garrapatas/prevención & control , Encefalitis Transmitida por Garrapatas/virología , Genoma Viral , Humanos , Macaca mulatta , Ratones , Neuronas/virología , Ratas , Ratas Endogámicas F344 , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Vacunas Atenuadas/genética , Células Vero , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Vacunas Virales/genética , Replicación ViralRESUMEN
Nivolumab and pembrolizumab, anti-programmed cell death protein 1 monoclonal antibodies, have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach, these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half-lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next, simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that >95% of patients maintained ≥1.5 µg/mL at steady state, which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in >95% of patients. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated, showing that >95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50%, thus substantially reducing patient visits (as well as costs), while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing, and ultimately an efficacy-driven comparative trial.
Asunto(s)
Antineoplásicos Inmunológicos , Nivolumab , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/farmacocinética , Simulación por Computador , Relación Dosis-Respuesta a Droga , Humanos , Nivolumab/farmacocinética , Estudios ProspectivosRESUMEN
Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the mortality of coronavirus disease 2019 (COVID-19). The IL-6 receptor-blocking monoclonal antibody tocilizumab has been repurposed for COVID-19, but prospective trials and dose-finding studies in COVID-19 have not yet fully reported. We conducted a single-arm phase II trial of low-dose tocilizumab in nonintubated hospitalized adult patients with COVID-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L. We hypothesized that doses significantly lower than the emerging standards of 400 mg or 8 mg/kg would resolve clinical and laboratory indicators of hyperinflammation. A dose range from 40 to 200 mg was evaluated, with allowance for one repeat dose at 24 to 48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Thirty-two patients received low-dose tocilizumab, with the majority experiencing fever resolution (75%) and CRP decline consistent with IL-6 pathway abrogation (86%) in the 24-48 hours following drug administration. There was no evidence of a relationship between dose and fever resolution or CRP decline over the dose range of 40-200 mg. Within the 28-day follow-up, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 3 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (16%) patients. Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with COVID-19. Results of this trial provide rationale for a randomized, controlled trial of low-dose tocilizumab in COVID-19.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Proteína C-Reactiva/análisis , Tratamiento Farmacológico de COVID-19 , COVID-19 , Fiebre , Neumonía Viral , Anciano , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Antiinflamatorios/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , COVID-19/sangre , COVID-19/fisiopatología , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Femenino , Fiebre/diagnóstico , Fiebre/tratamiento farmacológico , Humanos , Masculino , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/etiología , Receptores de Interleucina-6/antagonistas & inhibidores , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Background Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. Methods We conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) >= 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. Findings A total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75.0% vs. 34.2%, p = 0.001) and CRP decline (86.2% vs. 14.3%, p < 0.001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related in this small study (p=0.80 and p=0.10, respectively). Within the 28-day follow-up, 5 (15.6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15.6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. Interpretation Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.