RESUMEN
BACKGROUND: Carfilzomib is approved by the US Food and Drug Administration for the treatment of patients with relapsed and refractory multiple myeloma (MM) who have received at least 2 previous treatments. The approval was based on phase II trials that used a starting dose of 20 mg/m(2) escalated to a target dose of 27 mg/m(2) in cycle 2. We examined dose-outcome relationships in MM patients who received these 2 carfilzomib doses. MATERIALS AND METHODS: Patient data from 4 cohorts of MM patients treated with single-agent carfilzomib in phase II trials were examined post hoc. The relationship between administered doses and overall response rate (ORR) was assessed using logistic regression models. Secondary analyses were performed using Cox regression models to assess the association between administered doses and time to event outcomes and using generalized estimating equations for cycle-specific response status (CSRS). RESULTS: A total of 476 intention to treat patients were enrolled, 461 of whom were evaluable for efficacy. In the primary analysis, adjustment for cohort and baseline covariates yielded an odds ratio for ORR of 1.28 (95% confidence interval, 1.16-1.41; P < .001) for each 1 mg/m(2) increase in the average administered dose of carfilzomib per patient (up to 27 mg/m(2)). Qualitatively similar and statistically significant results were seen for the association between administered dose and CSRS, duration of response, time to progression, progression-free survival, and overall survival when adjusted for cohort and baseline covariates. CONCLUSION: This post hoc analysis provides evidence for a dose-response relationship between the administered dose of carfilzomib and efficacy.
Asunto(s)
Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Oligopéptidos/uso terapéutico , Inhibidores de Proteasoma/uso terapéutico , Antineoplásicos/administración & dosificación , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Mieloma Múltiple/mortalidad , Oligopéptidos/administración & dosificación , Inhibidores de Proteasoma/administración & dosificación , Recurrencia , Retratamiento , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab. EXPERIMENTAL DESIGN: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%). CONCLUSION: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Receptor ErbB-2/metabolismo , Enfermedades de la Piel/inducido químicamente , Sorafenib , Estomatitis/inducido químicamente , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND: We conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer. METHODS: Patients were randomised to paclitaxel (90mg/m(2), weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ≤ 0.82 (1-sided α=0.14) after 120 events supporting a treatment effect. FINDINGS: Patients were randomised in India (n=170), the United States (n=52) and Brazil (n=15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR)=0.788; 95% confidence interval (CI), 0.558-1.112; P=0.1715 [1-sided P=0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR=0.674; 95% CI 0.465-0.975; P=0.0343) and improved overall response (67% versus 54%; P=0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR=1.022; 95% CI 0.715-1.461; P=0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm. INTERPRETATION: The addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.