RESUMEN
BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).
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Neuropatías Amiloides Familiares/terapia , ARN Interferente Pequeño/uso terapéutico , Tratamiento con ARN de Interferencia , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/complicaciones , Progresión de la Enfermedad , Método Doble Ciego , Edema/inducido químicamente , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Infusiones Intravenosas/efectos adversos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Polineuropatías/etiología , Polineuropatías/terapia , Prealbúmina/análisis , Prealbúmina/genética , Calidad de Vida , ARN Interferente Pequeño/efectos adversos , Índice de Severidad de la Enfermedad , Prueba de PasoRESUMEN
BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).
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Neuropatías Amiloides Familiares/terapia , Prealbúmina/genética , ARN Interferente Pequeño/uso terapéutico , Adolescente , Adulto , Neuropatías Amiloides Familiares/genética , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Liposomas , Macaca fascicularis , Masculino , Nanocápsulas , Prealbúmina/metabolismo , ARN Interferente Pequeño/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment. METHODS: We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059. FINDINGS: Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001). INTERPRETATION: Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings. FUNDING: Alnylam Pharmaceuticals.
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LDL-Colesterol/sangre , Terapia Genética/métodos , Proproteína Convertasas/biosíntesis , ARN Interferente Pequeño/farmacología , Serina Endopeptidasas/biosíntesis , Adulto , LDL-Colesterol/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Terapia Genética/efectos adversos , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Proproteína Convertasa 9 , Proproteína Convertasas/sangre , Proproteína Convertasas/genética , Interferencia de ARN , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/efectos adversos , Serina Endopeptidasas/sangre , Serina Endopeptidasas/genética , Método Simple CiegoRESUMEN
Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .
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Dermatitis Atópica , Hidradenitis Supurativa , Humanos , Hidradenitis Supurativa/tratamiento farmacológico , Dermatitis Atópica/tratamiento farmacológico , Quinasas Asociadas a Receptores de Interleucina-1 , Resultado del Tratamiento , Piel/patología , Método Doble Ciego , Índice de Severidad de la EnfermedadRESUMEN
RATIONALE: Lower respiratory tract infections due to respiratory syncytial virus (RSV) are associated with development of bronchiolitis obliterans syndrome in lung transplant (LTX) recipients. ALN-RSV01 is a small interfering RNA targeting RSV replication. OBJECTIVES: To determine the safety and explore the efficacy of ALN-RSV01 in RSV infection. METHODS: We performed a randomized, double-blind, placebo-controlled trial in LTX recipients with RSV respiratory tract infection. Patients were permitted to receive standard of care for RSV. Aerosolized ALN-RSV01 (0.6 mg/kg) or placebo was administered daily for 3 days. Viral load was determined by quantitative reverse transcriptase-polymerase chain reaction on serial nasal swabs. Patients completed symptom score cards twice daily. Lung function, including the incidence of new-onset or progressive bronchiolitis obliterans syndrome, was recorded at Day 90. MEASUREMENTS AND MAIN RESULTS: We enrolled 24 patients (ALN-RSV01, n = 16; placebo, n = 8); randomization was stratified by ribavirin use. ALN-RSV01 was well tolerated, with no drug-related serious adverse events or post-inhalation perturbations in lung function. Interpretation of viral measures was confounded by baseline differences between the two groups in viral load and time from symptom onset to first dose. Mean daily symptom scores were lower in subjects receiving ALN-RSV01, and the mean cumulative daily total symptom score was significantly lower with ALN-RSV01 (114.7 ± 63.13 vs. 189.3 ± 99.59, P = 0.035). At Day 90, incidence of new or progressive bronchiolitis obliterans syndrome was significantly reduced in ALN-RSV01 recipients compared with placebo (6.3% vs. 50%, P = 0.027). CONCLUSIONS: ALN-RSV01 was safe and may have beneficial effects on long-term allograft function in LTX patients infected with RSV. Clinical trial registered with www.clinicaltrials.gov (NCT 00658086).
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Antivirales/uso terapéutico , Trasplante de Pulmón , Interferencia de ARN/efectos de los fármacos , ARN Interferente Pequeño/uso terapéutico , Infecciones por Virus Sincitial Respiratorio/terapia , Administración por Inhalación , Adolescente , Bronquiolitis Obliterante/complicaciones , Bronquiolitis Obliterante/prevención & control , Proteína C-Reactiva/efectos de los fármacos , Citocinas/sangre , Citocinas/efectos de los fármacos , Método Doble Ciego , Estudios de Seguimiento , Humanos , Pruebas de Función Respiratoria , Infecciones por Virus Sincitial Respiratorio/sangre , Infecciones por Virus Sincitial Respiratorio/complicaciones , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome , Resultado del Tratamiento , Adulto JovenRESUMEN
Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.
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Inmunoterapia , Neoplasias/terapia , Humanos , Cooperación Internacional , Investigación Biomédica TraslacionalRESUMEN
We conducted a single institution phase II trial to evaluate the tolerability and effectiveness of therapy with arsenic trioxide (ATO) and ascorbic acid (AA) with temozolomide (TMZ) in patients with advanced melanoma. Planned enrollment was for 40 patients. Eligible patients were required to have metastatic melanoma with or without brain metastases, an ECOG performance status of 0-2, and adequate organ function. The primary endpoints were overall response rate and degree of grade 4 toxicity. ATO was administered as a loading dose at 0.25 mg/kg/day for 5 days during week 0, and then twice weekly at 0.35 mg/kg during an 8-week cycle. Each infusion of ATO was followed by an infusion of 1000 mg of AA. TMZ was given at the standard dose of 200 mg/m for 5 days during weeks 1 and 5 of each cycle. Eleven patients were enrolled with 10 evaluable for response, five with central nervous system disease. No responses were seen among the first 10 patients and on the basis of a predetermined stopping rule, the trial was terminated. Common grade 1 and 2 side effects included nausea and vomiting (10), fatigue (six), edema (six), rash (six), and elevated AST or ALT (six). Grade 3 and 4 side effects included nausea and vomiting (three), elevated AST or ALT (two), seizure (one), and renal failure (one). This is the first trial combining ATO with chemotherapy in a solid tumor. ATO and AA were administered in the outpatient setting with TMZ in 11 patients with an acceptable side effect profile. No responses were seen in the first 10 evaluable patients leading to early closure of the study. Further studies using ATO and AA with TMZ with this dosing schedule in advanced melanoma are not warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arsenicales/uso terapéutico , Ácido Ascórbico/uso terapéutico , Neoplasias Encefálicas/secundario , Dacarbazina/análogos & derivados , Melanoma/tratamiento farmacológico , Melanoma/secundario , Óxidos/uso terapéutico , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Antioxidantes/uso terapéutico , Trióxido de Arsénico , Arsenicales/administración & dosificación , Arsenicales/efectos adversos , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Óxidos/administración & dosificación , Óxidos/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológico , TemozolomidaRESUMEN
PURPOSE: Metastatic uveal melanoma is resistant to conventional chemotherapy and immunotherapy. In this study, we investigated the responsiveness of uveal melanoma cell lines to IFNs and the hypomethylating agent decitabine. EXPERIMENTAL DESIGN: The uveal melanoma cell lines 92-1, UW-1, OCM-1, and MKT-BR were exposed to varying concentrations of IFN-alpha, IFN-gamma, and decitabine, alone and in combination. The effects of decitabine on gene expression were examined using DNA microarray analysis. RESULTS: We found that IFN-gamma and decitabine induced cell death in uveal melanoma. Whereas a high concentration of IFN-gamma (1,000 units/mL) was required to induce cell death, we observed a dose-related increase in cell death when decitabine was used at a range of 0.1 to 10 micromol/L. Strikingly, 1 micromol/L decitabine synergized with 10 to 1,000 units/mL IFN-gamma to induce massive cell death. In contrast, decitabine had no effect on three cutaneous melanoma cell lines and exhibited no synergy with either IFN. In uveal melanoma, decitabine up-regulated the expression of genes involved in growth control and apoptosis and down-regulated genes that have been implicated in the malignant phenotype of cutaneous melanoma. The gene up-regulated to the greatest degree by decitabine and whose expression showed a dose-effect across the three concentrations of decitabine was S100A2, a putative tumor suppressor. The genes modulated by decitabine in uveal melanoma were largely unaffected in cutaneous melanoma. CONCLUSIONS: These findings form a basis for testing the decitabine/IFN-gamma combination in metastatic uveal melanoma and for exploring the role of S100A2 in the susceptibility of uveal melanoma to IFN-mediated cell death.
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Antimetabolitos Antineoplásicos/farmacología , Azacitidina/análogos & derivados , Factores Quimiotácticos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interferón gamma/farmacología , Melanoma/tratamiento farmacológico , Proteínas S100/genética , Neoplasias de la Úvea/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Azacitidina/farmacología , Decitabina , Sinergismo Farmacológico , Humanos , Interferón-alfa/farmacología , Melanoma/metabolismo , Melanoma/patología , Células Tumorales Cultivadas , Neoplasias de la Úvea/metabolismo , Neoplasias de la Úvea/patologíaRESUMEN
PURPOSE: The silencing of gene expression through DNA methylation contributes to defects in antigen presentation and apoptosis in melanoma and renal cell cancer. To determine how a hypomethylating agent would modulate the toxicity and antitumor activity of immunotherapy, we initiated a phase I trial of 5-aza-2'-deoxycytidine (decitabine) plus high-dose interleukin 2 (IL-2). EXPERIMENTAL DESIGN: Patients received s.c. decitabine daily x 5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg i.v. q8 hours x 14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. The hypomethylating activity of decitabine was assessed during cycle 1 by measuring hemoglobin F levels and changes in DNA methylation in peripheral blood mononuclear cells. RESULTS: Twenty-one patients with melanoma or renal cell cancer were enrolled. Decitabine did not alter the tolerability of IL-2 but caused grade 4 neutropenia in most patients. Grade 4 neutropenia lasting more than 7 days was the only dose-limiting toxicity, with a trend toward a higher incidence with increasing decitabine doses. Infection occurred in only one patient despite the high incidence of neutropenia, and granulocyte colony-stimulating factor use in several patients expedited neutrophil recovery. Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a dose-independent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients. CONCLUSIONS: Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/análogos & derivados , Carcinoma de Células Renales/tratamiento farmacológico , Interleucina-2/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/farmacología , Metilación de ADN/efectos de los fármacos , Decitabina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Hemoglobina Fetal/efectos de los fármacos , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Interleucina-2/efectos adversos , Interleucina-2/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
IFN-gamma plays a role in the response to melanoma indirectly through its effect on the immune system and directly through its antiproliferative and proapoptotic effects on melanoma cells. To understand the molecular basis for the direct antimelanoma effect of IFN-gamma, we studied IFN-induced changes in gene expression and signaling among three human melanoma cell lines (DM6, DM93, and 501mel). These were resistant to the antimelanoma effect of IFN-alpha, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-gamma. Through DNA microarray analysis, we found that the antimelanoma effect of IFN-gamma in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2). The antimelanoma effect of IFN-gamma was also associated with the up-regulation of the proapoptotic dependence receptor UNC5H2 and the Wnt inhibitor Dkk-1. Whereas both IFNs were able to activate Stat1 in all cell lines, the delayed activation of the extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases occurred only in DM6 with IFN-gamma, and the effect of IFN-gamma on cell growth and survival as well as gene expression in DM6 was dependent on the coordinate activation of MEK1 and p38. These findings provide new insights into the signaling events and gene expression changes associated with growth inhibition and apoptosis in melanoma and may thereby assist in identifying new targets for the treatment of melanoma.
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Antineoplásicos/farmacología , Interferón gamma/farmacología , Melanoma/tratamiento farmacológico , Melanoma/genética , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Adhesión Celular/efectos de los fármacos , Adhesión Celular/fisiología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Activación Enzimática , Expresión Génica/efectos de los fármacos , Humanos , Interferón alfa-2 , Interferón-alfa/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , MAP Quinasa Quinasa 1/biosíntesis , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , Melanoma/enzimología , Melanoma/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Recombinantes , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteínas Wnt/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. RESULTS: One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. CONCLUSION: This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.
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Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Interleucina-2/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Inyecciones Subcutáneas , Interferón alfa-2 , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Recombinantes , Tasa de SupervivenciaRESUMEN
Improvements in our understanding of the molecular basis of cancer have led to the clinical development of protein kinase inhibitors, which target pivotal molecules involved in intracellular signaling pathways implicated in tumorigenesis and progression. These novel targeted agents have demonstrated activity against a wide range of solid tumors, are generally better tolerated than standard chemotherapeutics, and may revolutionize the management of advanced refractory cancer. The ubiquitous Raf serine/threonine kinases are pivotal molecules within the Raf/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which regulates cellular proliferation and survival. Raf kinase isoforms (wild-type Raf-1 or the b-raf V600E oncogene) are overactivated in a variety of solid tumor types, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), melanoma, and papillary thyroid carcinoma. In this review, the role of Raf in normal cells and in cancer is discussed, and an overview is given of Raf inhibitors currently in development, focusing on sorafenib tosylate (BAY 43-9006 or sorafenib). Sorafenib is the first oral multi-kinase inhibitor to be developed that targets Raf kinases (Raf-1, wild-type B-Raf, and b-raf V600E), in addition to receptor tyrosine kinases associated with angiogenesis (vascular endothelial growth factor receptor [VEGFR]-2/-3, platelet-derived growth factor receptor [PDGFR]-beta) or tumor progression (Flt-3, c-kit). Preclinical and clinical sorafenib data that led to its recent approval for the treatment of advanced RCC are summarized, along with current thinking on sorafenib's mechanism of effect on the tumor and tumor vasculature in melanoma and RCC.
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Antineoplásicos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Neoplasias/fisiopatología , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Quinasas raf/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Transformación Celular Neoplásica/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/química , Melanoma/tratamiento farmacológico , Ratones , Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Isoformas de Proteínas , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Sorafenib , Quinasas raf/químicaRESUMEN
Although improved survival is the "gold standard" for proving clinical benefit of oncologic therapy, the U.S. Food and Drug Administration (FDA) has accepted significant results in clinical trials using surrogate endpoints as the basis for drug approval. One surrogate is the amount of tumor reduction, or tumor response. Although tumor shrinkage would seem to be a necessary precondition for improved survival, clinical studies of a variety of oncologic agents have not consistently demonstrated a correlation between the two in patients with renal cell carcinoma. Moreover, tumor response may not be an appropriate endpoint for evaluating the effects of the new targeted therapies, whose putative mechanisms are generally cytostatic rather than cytotoxic. Clinical trials suggest that some patients with other solid tumors, such as lung cancer, may derive clinical benefit from treatment that helps stabilize their disease. There is also controversy as to whether the Response Evaluation Criteria in Solid Tumors (RECIST) provides the most appropriate instrument for assessing tumor burden. Ultimately, use of a variety of endpoints as well as different trial designs may provide an adequate basis for investigating the benefits/risks of newer therapies.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Ensayos Clínicos como Asunto/métodos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Antineoplásicos/farmacología , Carcinoma de Células Renales/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Aprobación de Drogas , Determinación de Punto Final , Humanos , Neoplasias Renales/patología , Neoplasias Pulmonares/patología , Melanoma/patología , Estados Unidos , United States Food and Drug AdministrationRESUMEN
PURPOSE: To maintain interferon gamma (IFNgamma) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study. PATIENTS AND METHODS: Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU/m2. Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12. RESULTS: Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng/kg rhIL-12 plus 3 MU/m2 IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFNgamma and IFNgamma-inducible protein-10 production by rhIL-12 and led to a three-fold expansion of natural killer cells. There was one major clinical response (partial response) as well as two pathologic responses; all occurred in melanoma patients. Stable disease for three to six cycles was only observed at or above the MTD in melanoma and renal cell cancer patients. CONCLUSION: The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12-responsive malignancies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/patología , Esquema de Medicación , Femenino , Humanos , Inyecciones Subcutáneas , Interleucina-12/administración & dosificación , Interleucina-2/administración & dosificación , Masculino , Dosis Máxima Tolerada , Melanoma/patología , Persona de Mediana Edad , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
PURPOSE: To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. PATIENTS AND METHODS: The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. RESULTS: Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. CONCLUSION: ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.
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Anticuerpos Monoclonales/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Fosfatasa Alcalina/sangre , Anticuerpos Antiidiotipos/sangre , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/toxicidad , Carcinoma de Células Renales/metabolismo , Erupciones por Medicamentos/etiología , Femenino , Estudios de Seguimiento , Hemoglobinas/análisis , Humanos , Inmunohistoquímica , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Panitumumab , SeguridadRESUMEN
Clear-cell renal cell carcinoma (RCC) is characterized by the loss of von Hippel-Lindau disease protein and the resultant dysregulation of the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), platelet-derived growth factor-beta (PDGF-beta)/PDGF receptor-beta (PDGFR-beta), and transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGFR)/Raf pathways, which contribute to angiogenesis, lymphangiogenesis, and tumor cell growth and survival. Significant advances in the treatment of clear-cell RCC have been derived from agents that target these pathways, including the multiple-kinase inhibitors (MKIs) sorafenib, sunitinib, and AG013736, which target multiple VEGFRs as well as PDGFR-beta. Sorafenib has the added advantage of inhibiting multiple different Raf isoforms, which enables it to target TGF-alpha/EGFR signaling and may also enhance its inhibition of VEGFR and PDGFR-beta. This review will examine the recent advances in our understanding of the biology of clear-cell RCC and show how those advances have helped delineate new targets of opportunity for treatment. It will also present the early clinical results of agents that target the pathways dysregulated in clear-cell RCC, with special emphasis on sorafenib and the other active MKIs, and will describe the scientific rationales for ongoing and future sorafenib-based combination therapy trials in RCC.
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Antineoplásicos/farmacología , Bencenosulfonatos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/metabolismo , Receptores ErbB/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Neoplasias Renales/metabolismo , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-sis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-sis/metabolismo , Piridinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sorafenib , Factor de Crecimiento Transformador alfa/efectos de los fármacos , Factor de Crecimiento Transformador alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/efectos de los fármacos , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
PURPOSE: In an effort to reduce the frequency of central nervous system (CNS) progression in patients with metastatic melanoma with ongoing systemic response to biochemotherapy, we modified our standard concurrent biochemotherapy regimen by replacing dacarbazine (DTIC) with oral temozolomide. EXPERIMENTAL DESIGN: Patients received cisplatin, vinblastine, and temozolomide (20 mg/m(2) cisplatin and 1.2 mg/m(2) vinblastine i.v., days 1-4; 150 mg/m(2) p.o. temozolomide, days 1-4) concurrent with interleukin 2 (9 MIU/m(2)/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m(2)/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte-colony stimulating factor and aggressive antiemetics were also provided. Tumor staging included torso computed tomography scans and brain magnetic resonance imaging pretreatment, after cycle 4 and then every 3 months for 2 years. Torso computed tomography scans were also performed after cycle 2. RESULTS: A total of 147 treatment cycles were administered to 48 patients. No patients had received prior chemotherapy or interleukin 2; however, 19 (40%) had received prior adjuvant IFN-alpha. Significant toxicities included 2 deaths from cardiac events (pericarditis al tamponade and posttreatment myocardial infarction with associated ventricular arrhythmia) and 3 gastrointestinal serious adverse events (pancreatitis, appendicitis, and upper GI bleed). No other nonhematological grade 4 toxicities were observed. Tumor responses were seen in 22 of 47 evaluable patients (relative risk, 47%) with 7 complete responses (15%). Response durations ranged from 1 to 29+ months with 1 currently ongoing. Median survival was 7.5 months. The CNS was the initial site of progression in 2 responding patients. An additional 6 responding patients developed CNS progression within 3 months of systemic progression. Initial CNS progression was significantly less frequent what was seen with the prior DTIC-based biochemotherapy regimen (2 of 22 versus 12 of 19; P = 0.001). CONCLUSION: This regimen appears to be active and reasonably well tolerated in patients with metastatic melanoma. Although the substitution of temozolomide for DTIC reduced the incidence of initial CNS progression, this effect did not appear to result in an improved overall outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Melanoma/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Infusiones Intravenosas , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Masculino , Melanoma/secundario , Persona de Mediana Edad , Proyectos Piloto , Proteínas Recombinantes , Temozolomida , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/efectos adversosRESUMEN
OBJECTIVES: To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP). METHODS: We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models. RESULTS: For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin (TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p < 0.0001) and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p < 0.0001). In addition, there was an association between NIS and TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8 points/year. CONCLUSIONS: In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion.
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Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/epidemiología , Progresión de la Enfermedad , Índice de Severidad de la Enfermedad , Adulto , Edad de Inicio , Anciano , Neuropatías Amiloides Familiares/genética , Estudios Transversales , Femenino , Francia/epidemiología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Portugal/epidemiología , Estados Unidos/epidemiologíaRESUMEN
UNLABELLED: RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer. SIGNIFICANCE: The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology.
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Cinesinas/genética , Neoplasias Hepáticas/terapia , Nanopartículas/administración & dosificación , Interferencia de ARN , ARN Interferente Pequeño/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Animales , Línea Celular Tumoral , Citocinas/sangre , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , ARN Mensajero/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The emerging class of RNA interference (RNAi) therapeutics is a fundamentally novel approach to treating human disease by enabling the pursuit of molecular targets considered "undruggable" by small molecules and traditional protein therapeutics. A key challenge toward realizing the full potential of this technology is the safe and efficient delivery of siRNA to target tissues. The physical chemical properties of siRNAs preclude passive diffusion across most cell membranes. For systemic administration, novel delivery systems are required to confer "drug-like" pharmacokinetic and pharmacodynamic properties. Engineered nanomaterials and the emerging field of nanomedicine are important drivers of turning the promise of RNAi therapeutics into reality. The current clinical progress of systemically administered siRNA therapeutics is reviewed, with special attention to the toxicity profiles associated with RNAi nanomedicines. As a case study, the preclinical development of ALN-VSP, the first lipid nanoparticle (LNP)-formulated siRNA therapeutic to be tested in cancer patients, is reviewed to broadly highlight some of the preclinical safety challenges and areas of investigation for "next generation" LNP systems.