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BACKGROUND: Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS: Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5-fluorouracil 2,400 mg/m2: irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2, folinic acid 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3). The RP2D was further evaluated in safety expansion cohorts. Preliminary antitumour activity was also assessed. RESULTS: Ninety-two patients received ≥1 veliparib dose. MTD was not reached; RP2D was set at 200 mg BID veliparib plus FOLFIRI (without 5-fluorouracil bolus). Most common treatment-emergent adverse events were neutropenia (66.3%), diarrhoea, and nausea (60.9% each). Dose-limiting toxicities (n = 4) were grade 3 gastritis and grade 4 neutropenia and febrile neutropenia. Veliparib exposure was dose-proportional, with no effects on the pharmacokinetics of FOLFIRI components. Fifteen patients had a partial response (objective response rate, 17.6%). CONCLUSIONS: The acceptable safety profile and preliminary antitumour activity of veliparib plus FOLFIRI support further evaluation of this combination.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bencimidazoles/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bencimidazoles/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Humanos , Leucovorina/administración & dosificación , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy. METHODS: MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors. RESULTS: Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%). CONCLUSIONS: Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage-SCLC.
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Inmunoconjugados , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzodiazepinonas/uso terapéutico , Método Doble Ciego , Humanos , Inmunoconjugados/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Persona de Mediana Edad , Platino (Metal)/uso terapéuticoRESUMEN
Purpose: PARP plays an important role in DNA repair. Veliparib, a PARP inhibitor, enhances the efficacy of platinum compounds and has been safely combined with carboplatin and paclitaxel. The primary endpoint of this phase II trial determined whether addition of veliparib to carboplatin and paclitaxel improved progression-free survival (PFS) in previously untreated patients with advanced/metastatic non-small cell lung cancer.Experimental Design: Patients were randomized 2:1 to carboplatin and paclitaxel with either veliparib or placebo. Veliparib (120 mg) or placebo was given on days 1 to 7 of each 3-week cycle, with carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m2) administered on day 3, for a maximum of 6 cycles.Results: Overall, 158 were included (median age, 63 years; male 68%, squamous histology 48%). Median PFS was 5.8 months in the veliparib group versus 4.2 months in the placebo group [HR, 0.72; 95% confidence interval (CI), 0.45-1.15; P = 0.17)]. Median overall survival (OS) was 11.7 and 9.1 months in the veliparib and placebo groups, respectively (HR, 0.80; 95% CI, 0.54-1.18; P = 0.27). In patients with squamous histology, median PFS (HR, 0.54; 95% CI, 0.26-1.12; P = 0.098) and OS (HR, 0.73; 95% CI, 0.43-1.24; P = 0.24) favored veliparib treatment. Objective response rate was similar between groups (veliparib: 32.4%; placebo: 32.1%), but duration of response favored veliparib treatment (HR, 0.47; 95% CI, 0.16-1.42; P = 0.18). Grade III/IV neutropenia, thrombocytopenia, and anemia were comparable between groups.Conclusions: Veliparib combination with carboplatin and paclitaxel was well-tolerated and demonstrated a favorable trend in PFS and OS versus chemotherapy alone. Patients with squamous histology had the best outcomes with veliparib combination. Clin Cancer Res; 23(8); 1937-44. ©2016 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Bencimidazoles/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
INTRODUCTION: Tobacco-related NSCLC is associated with reduced survival and greater genomic instability. Veliparib, a potent poly(adenosine diphosphate-ribose) polymerase inhibitor, augments platinum-induced DNA damage. A phase 2 trial of untreated advanced NSCLC showed a trend for improved outcomes (hazard ratio [HR] = 0.80, 95% confidence interval: 0.54-1.18, p = 0.27 for overall survival and HR = 0.72, 95% CI: 0.45-1.15, p = 0.17 for progression-free survival) when veliparib was added to carboplatin/paclitaxel. Here we report an exploratory analysis by smoking history. METHODS: Patients were randomized 2:1 to receive carboplatin/paclitaxel with veliparib, 120 mg (n = 105), or placebo (n = 53). Patients were stratified by histologic subtype and smoking history (recent smokers [n = 95], former smokers [n = 42], and never-smokers [n = 21]). Plasma cotinine level was measured as a chemical index of smoking. Mutation status was assessed by whole exome sequencing (n = 38). RESULTS: Smoking history, histologic subtype, age, Eastern Cooperative Oncology Group performance status, sex, and geographic region predicted veliparib benefit in univariate analyses. In multivariate analysis, history of recent smoking was most predictive for veliparib benefit. Recent smokers treated with veliparib derived significantly greater progression-free survival and overall survival benefits (HR = 0.38 [p < 0.01] and HR = 0.43 [p < 0.01]) than former smokers (HR = 2.098 [p = 0 0208] and HR = 1.62 [p = 0.236]) and never-smokers (HR = 1.025 [p = 0.971] and HR = 1.33 [p = 0.638]). Sequencing data revealed that mutational burden was not associated with veliparib benefit. The rate of grade 3 or 4 adverse events was higher in recent smokers with veliparib treatment; all-grade and serious adverse events were similar in both treatment arms. CONCLUSIONS: Smoking history predicted for efficacy with a veliparib-chemotherapy combination; toxicity was acceptable regardless of smoking history. A prespecified analysis of recent smokers is planned for ongoing phase 3 studies of veliparib in NSCLC.
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Bencimidazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Fumar/efectos adversos , Anciano , Bencimidazoles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Método Doble Ciego , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
BACKGROUND: Endothelial dysfunction contributes to the development of intimal hyperplasia in transplanted hearts by decreasing the protective effects of endothelial-derived nitric oxide. Immunosuppressive drugs may increase the dysfunction caused by rejection and further accelerate the development of graft coronary vasculopathy. This study compares the effect of cyclosporine and tacrolimus vs two newer immunosuppressive drugs, mycophenolate mofetil and rapamycin, on coronary endothelial function. METHODS: An in vitro model of drug incubation in Krebs-bicarbonate solution (4(o)C, 48 hours) using porcine epicardial coronary arteries was developed. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4), 10(-7) mol/liter), tacrolimus (10(-4), 10(-7) mol/liter), mycophenolate mofetil (10(-4), 10(-7) mol/liter), rapamycin (10(-7), 10(-11) mol/liter), and their vehicles to assess effects on G-protein-mediated vasorelaxations leading to the release of nitric oxide. RESULTS: Exposure to cyclosporine and mycophenolate mofetil was associated with a dose-dependent decrease in endothelium-dependent relaxations to serotonin (an agonist that binds to 5-HT1D receptors coupled to Gi-protein) but no impairment of relaxations to bradykinin (an agonist that binds to B2 receptors coupled to Gq-proteins). Exposure to tacrolimus and rapamycin caused severe impairment of relaxations to serotonin and a lesser one to bradykinin. We observed alterations of relaxations to the calcium ionophore A23187 after exposure to mycophenolate mofetil and rapamycin. Exposure to rapamycin and mycophenolate mofetil vehicles impaired relaxation to all agonists. CONCLUSIONS: These results suggest that cyclosporine and mycophenolate mofetil induce a dysfunction of the vasorelaxing properties of the endothelium that may lead to a decrease in the protective effects of nitric oxide on the vascular wall but that these drugs still have a more favorable vascular profile than do tacrolimus and rapamycin. Decreased endothelial function after mycophenolate mofetil and rapamycin exposure could be caused by their vehicles.