RESUMEN

The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ⩾2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (⩾2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide.

Asunto(s)

Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Oligopéptidos/administración & dosificación , Terapia Recuperativa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Supervivencia sin Enfermedad , Humanos , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Oligopéptidos/uso terapéutico , Recurrencia , Terapia Recuperativa/mortalidad , Resultado del Tratamiento

RESUMEN

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adulto , Biomarcadores de Tumor , Bortezomib/administración & dosificación , Aberraciones Cromosómicas , Análisis Citogenético , Dexametasona/administración & dosificación , Resistencia a Antineoplásicos/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Clasificación del Tumor , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Oligopéptidos/administración & dosificación , Pronóstico , Inducción de Remisión , Tasa de Supervivencia

RESUMEN

BACKGROUND: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. PATIENTS AND METHODS: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. RESULTS: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. CONCLUSIONS: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/secundario , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Gemcitabina

RESUMEN

PURPOSE: Carboplatin is frequently dosed to achieve a desired area under the plasma concentration-time curve (AUC) by using the Calvert or Chatelut equations to estimate carboplatin clearance. Accurate determination of glomerular filtration rate (GFR) is necessary to correctly calculate carboplatin clearance using the Calvert equation. In clinical practice, the Cockcroft-Gault formula is frequently used to estimate GFR, but this practice has been reported to under- and overestimate carboplatin clearance. The purpose of this trial was to compare determinations of carboplatin clearance using the Chatelut equation and four separate GFR determinations, including 99mTc-DTPA, the Cockcroft-Gault formula, a 24-h urine collection and a 2-h urine collection. METHODS: Carboplatin clearance was estimated in 21 previously untreated extensive-stage small-cell lung cancer patients. GFR was determined using 99mTc-DTPA, the Cockcroft-Gault formula, 24-h urine collection and 2-h urine collection. Serum and urine creatinine concentrations were measured using enzymatic assays. The carboplatin clearance was then calculated by individually adding 25 to the four GFR determinations based on the Calvert equation, which states that carboplatin clearance equals GFR + 25 (nonrenal clearance). The carboplatin clearance was also estimated using the Chatelut equation. The five determinations of carboplatin clearance were compared using Friedman's test and post-hoc Wilcoxon signed rank tests. Precision and bias for each carboplatin clearance determination were calculated assuming that 99mTc-DTPA provided the most accurate measure of GFR. RESULTS: A statistically significant difference was found between the five methods of estimating carboplatin clearance (P < 0.001). No difference was found between carboplatin clearance calculated using 99mTc-DTPA and the Chatelut equation, the Cockcroft-Gault formula or the 2-h urine collection. The Chatelut equation provided more precision and less bias than the 2-h urine collection (median precision 20% and 30%, median bias -1% and -18%, respectively). CONCLUSION: Compared to 99mTc-DTPA, the Chatelut equation more accurately estimates carboplatin clearance than the Cockcroft-Gault formula, the 2-h urine collection and the 24-h urine collection. The greater negative bias found for the latter three estimates of carboplatin clearance could result in underdosing of carboplatin.

Asunto(s)

Antineoplásicos/farmacocinética , Carboplatino/farmacocinética , Creatinina/metabolismo , Tasa de Filtración Glomerular , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos/orina , Área Bajo la Curva , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carboplatino/orina , Carcinoma de Células Pequeñas/tratamiento farmacológico , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pentetato de Tecnecio Tc 99m

RESUMEN

PURPOSE: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures. METHODS: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone. RESULTS: The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59). CONCLUSIONS: These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.

Asunto(s)

Sistema Enzimático del Citocromo P-450/biosíntesis , Dexametasona/farmacología , Dextrometorfano/análogos & derivados , Glucocorticoides/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Oxigenasas de Función Mixta/biosíntesis , Administración Oral , Adulto , Antiinflamatorios/farmacología , Pruebas Respiratorias/métodos , Células Cultivadas , Citocromo P-450 CYP3A , Dexametasona/administración & dosificación , Dexametasona/sangre , Dextrometorfano/orina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inducción Enzimática/efectos de los fármacos , Eritromicina/análisis , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/sangre , Humanos , Hidroxilación/efectos de los fármacos , Técnicas In Vitro , Masculino , Valor Predictivo de las Pruebas , Valores de Referencia , Testosterona/metabolismo

RESUMEN

Two recent trials have suggested that docetaxel improves survival in the second-line treatment of non small-cell lung cancer (NSCLC) refractory to first-line platinum-based regimens. Given this, it is appropriate to continue to address the role of new agents in the second-line treatment of refractory NSCLC. Gemcitabine is a well-tolerated new agent that has been shown to have activity in NSCLC. Thirty-one previously treated patients with NSCLC were entered in this study. Eight patients had responsive disease (defined as response to first-line therapy lasting greater than or equal to 3 months) and 23 had refractory disease (defined as progressive disease on first-line therapy or progression less than 3 months from completing first-line therapy). Gemcitabine (1250 mg/m2) was infused over 30 minutes on days 1, 8, and 15 every 28 days. Quality of life (QOL) was assessed with each cycle using the Functional Assessment Cancer Therapy-Lung (FACT-L) questionnaire. Two patients (6.5%) had a partial response, and nine (29%) had disease stabilization. The most frequent grade 3/4 toxicity was myelosuppression, but this only occurred in 8% of doses delivered. Fifty-two percent of evaluable patients had stable or improved QOL over baseline, 10% had a decline in QOL, and the remainder completed only baseline questionnaires. Twenty-nine patients have died of progressive NSCLC; two patients remain alive. Overall, the 31 patients have a median survival of 5.1 months (95% confidence interval [CI]: 4.2-7.4 months) and 1-year survival rate of 16% (95% CI: 3%-29%). Gemcitabine was well tolerated in this patient population. An objective response rate of 6.5% was observed although a significant proportion of patients (29%) experienced stable disease, which may have impacted on their survival. QOL was improved or maintained in over half of the patients. Given these data, gemcitabine as a single agent is a therapeutic option for patients with refractory NSCLC.