RESUMO
Congenital sideroblastic anemia (CSA) is a group of disorders caused by different genetic mutations that result in low iron utilization and ineffective erythropoiesis. Current treatments are limited, and some patients do not respond to vitamin B6 therapy. Luspatercept is a novel erythropoietic maturation agent approved for adult ß-thalassemia and Myelodysplastic syndromes with ring sideroblasts (MDS-RS) associated with ineffective erythropoiesis. Here we report 2 patients with CSA due to mutations in ALAS2 and SLC25A38 genes who became unresponsive after a period of treatment with vitamin B6 and iron chelators but achieved transfusion independence and a markedly reduced spleen after combination with luspatercept.
Assuntos
Receptores de Activinas Tipo II , Anemia Sideroblástica , Doenças Genéticas Ligadas ao Cromossomo X , Proteínas Recombinantes de Fusão , Adulto , Humanos , 5-Aminolevulinato Sintetase , Receptores de Activinas Tipo II/efeitos adversos , Anemia Sideroblástica/tratamento farmacológico , Anemia Sideroblástica/genética , Anemia Sideroblástica/congênito , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Vitamina B 6RESUMO
Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta-thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT-associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of ≥10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often-serious disease-associated complications. However, appropriate follow-up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept-associated erythroid expansion.
Assuntos
Receptores de Activinas Tipo II , Talassemia beta , Adulto , Humanos , Receptores de Activinas Tipo II/efeitos adversos , Receptores de Activinas Tipo II/uso terapêutico , Talassemia beta/complicações , Talassemia beta/diagnóstico , Talassemia beta/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
Luspatercept (Reblozyl®), a first-in-class erythroid maturation agent, is approved in several countries worldwide for the treatment of adults with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS), who have failed prior erythropoiesis-stimulating therapy, or ß-thalassaemia. In pivotal, placebo-controlled, phase III trials, subcutaneous luspatercept significantly reduced red blood cell (RBC) transfusion requirements in patients with MDS or ß-thalassaemia. Luspatercept had a generally manageable tolerability profile in clinical trials. Adverse events of special interest include thromboembolic events, hypertension and bone pain. Thus, luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS or ß-thalassaemia.
Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Anemia/etiologia , Transfusão de Eritrócitos/efeitos adversos , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Síndromes Mielodisplásicas/terapia , Proteínas Recombinantes de Fusão/uso terapêutico , Talassemia beta/terapia , Receptores de Activinas Tipo II/efeitos adversos , Receptores de Activinas Tipo II/farmacologia , Ensaios Clínicos Fase III como Assunto , Hematínicos/efeitos adversos , Hematínicos/farmacologia , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologiaRESUMO
Introduction: Beta-thalassemia is an autosomal recessive hereditary anemia characterized by reduced or absent ß-globin chain synthesis, affecting about 60,000 people peryear. Management for ß-thalassemia major includes regular blood transfusions followed by iron chelating therapy and drug targeting ineffective erythropoiesis.Areas covered: The safety of licensed drugs for the management of ß-thalassemia is reviewed, using evidence from clinical trials and observational research. Such drugs include the iron chelators and the erythrocyte maturation agent luspatercept. The safety of emerging treatment, such as hydroxyurea and thalidomide is also reviewed.Expert opinion: Beta-thalassemia is arare disease, and is not surprising that there are limited studies investigating the safety of drugs used in this disease. Indeed, although observational studies are the main source of drug safety information in areal-world setting, only eleven studies were identified for iron-chelators and none of these estimated the risk of agiven safety outcome. Future work should aim to better leverage existing sources of real-world datato investigate drug safety in thalassemia.
Assuntos
Receptores de Activinas Tipo II/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Quelantes de Ferro/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Talassemia beta/tratamento farmacológico , Receptores de Activinas Tipo II/administração & dosagem , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Quelantes de Ferro/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talassemia beta/fisiopatologiaRESUMO
Luspatercept is a recombinant fusion protein that enhances late-stage erythroid maturation. This report describes the population pharmacokinetics and exposure-response relationship of luspatercept in 260 patients with anemia due to myelodysplastic syndromes. Luspatercept displayed linear and time-invariant pharmacokinetics over a dose range of 0.125-1.75 mg/kg administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept exposure, supporting the weight-based dosing. The probability of achieving transfusion independence ≥ 8 weeks increased with time-averaged luspatercept serum exposure, reaching the plateau at doses 1.0-1.75 mg/kg. The probability of achieving multiple efficacy end points increased with slower luspatercept clearance, independent of effects of luspatercept exposure or disease characteristics. The probability of experiencing severe treatment-emergent adverse events decreased with increasing luspatercept exposure, especially during long-term treatment. These results provide a positive benefit-risk profile for the titration-to-response dose regimen (1.0-1.75 mg/kg) recommended for this population.
Assuntos
Receptores de Activinas Tipo II/administração & dosagem , Anemia/tratamento farmacológico , Hematínicos/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Receptores de Activinas Tipo II/efeitos adversos , Receptores de Activinas Tipo II/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Relação Dose-Resposta a Droga , Feminino , Hematínicos/efeitos adversos , Hematínicos/farmacocinética , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).
Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Transfusão de Eritrócitos/estatística & dados numéricos , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Talassemia beta/tratamento farmacológico , Receptores de Activinas Tipo II/efeitos adversos , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Ferritinas/sangue , Hematínicos/efeitos adversos , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Análise de Intenção de Tratamento , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Razão de Chances , Proteínas Recombinantes de Fusão/efeitos adversos , Esplenectomia , Adulto Jovem , Talassemia beta/genética , Talassemia beta/cirurgia , Talassemia beta/terapiaRESUMO
BACKGROUND: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor ß superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).
Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Anemia Sideroblástica/tratamento farmacológico , Transfusão de Eritrócitos , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Sideroblástica/terapia , Método Duplo-Cego , Feminino , Hematínicos/efeitos adversos , Hemoglobinas/análise , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Proteínas Recombinantes de Fusão/efeitos adversosRESUMO
BACKGROUND: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.
Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/administração & dosagem , Receptores de Activinas Tipo II/efeitos adversos , Receptores de Activinas Tipo II/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Axitinibe/administração & dosagem , Axitinibe/efeitos adversos , Carcinoma de Células Renais/mortalidade , Diarreia/etiologia , Método Duplo-Cego , Fadiga/etiologia , Feminino , Humanos , Hipertensão/etiologia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/metabolismo , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/metabolismoRESUMO
OBJECTIVE: To determine the efficacy of dalantercept, a soluble ALK1 inhibitor receptor fusion protein, in patients with persistent or recurrent ovarian carcinoma and related malignancies. METHODS: Eligibility criteria included measurable disease, 1-2 prior cytotoxic regimens and GOG performance status (PS) ≤2. Dalantercept was administered subcutaneously at 1.2â¯mg/kg every 3â¯weeks until disease progression or development of unacceptable toxicity. The primary null hypothesis was the probability of response ≤0.10 and the probability of 6-month progression-free survival without receipt of non-protocol therapy (event-free survival at 6â¯months, EFS6) ≤0.15, using RECIST 1.1 criteria. RESULTS: The first stage was closed after enrollment of 30 participants with median age of 56.5â¯years, high-grade serous histology in 76.7%, 2 prior regimens in 46.7%, and platinum-free interval <6â¯months in 73.3%. All participants discontinued dalantercept, 24 (80.0%), 5 (16.7%) and 1 (3.3%) due to progression, toxicity, and other reason, respectively. The median number of treatment cycles per patient was 2 (range 1-29). There were six treatment-related grade 3 AEs and no grade ≥4 AEs. There were no objective responses. EFS6 was reached in 20% (6 out of 30 participants, 90% CI 9.1% to 35.7%). CONCLUSIONS: Though safe, dalantercept as administered had limited efficacy in this patient population overall.
Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/efeitos adversos , Adulto , Idoso , Antineoplásicos/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Pessoa de Meia-Idade , Neoplasia Residual , Proteínas Recombinantes de Fusão/efeitos adversos , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
Purpose: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and VEGF signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1-receptor fusion protein that acts as a ligand trap for bone morphogenetic proteins 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing.Experimental Design: Patients received dalantercept 0.6, 0.9, or 1.2 mg/kg subcutaneously every 3 weeks plus axitinib 5 mg by mouth twice daily until disease progression or intolerance.Results: Twenty-nine patients were enrolled in the dose escalation (n = 15) and expansion (n = 14) cohorts. There were no dose-limiting toxicities or grade 4/5 treatment-related adverse events. In addition to common VEGFR tyrosine kinase inhibitor effects, such as fatigue and diarrhea, commonly seen treatment-related adverse events were peripheral edema, epistaxis, pericardial effusion, and telangiectasia. The objective response rate by RECIST v1.1 was 25% with responses seen at all dose levels. The overall median progression-free survival was 8.3 months.Conclusions: The combination of dalantercept plus axitinib is well tolerated and associated with clinical activity. On the basis of safety and efficacy results, the 0.9 mg/kg dose level was chosen for further study in a randomized phase II trial of dalantercept plus axitinib versus placebo plus axitinib. Clin Cancer Res; 23(14); 3557-65. ©2016 AACR.
Assuntos
Receptores de Activinas Tipo II/administração & dosagem , Receptores de Activinas Tipo II/genética , Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Indazóis/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/genética , Receptores de Activinas Tipo II/efeitos adversos , Receptores de Activinas Tipo II/antagonistas & inibidores , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
OBJECTIVE: This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). METHODS: Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. RESULTS: All 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively. CONCLUSIONS: Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.
Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/efeitos adversos , Adulto , Idoso , Intervalo Livre de Doença , Neoplasias do Endométrio/irrigação sanguínea , Neoplasias do Endométrio/patologia , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neovascularização Patológica/tratamento farmacológico , Proteínas Recombinantes de Fusão/efeitos adversosRESUMO
ACE-536, a recombinant protein containing a modified activin receptor type IIB, is being developed for the treatment of anemias caused by ineffective erythropoiesis, such as thalassemias and myelodysplastic syndromes. ACE-536 acts through a mechanism distinct from erythropoiesis-stimulating agents to promote late-stage erythroid differentiation by binding to transforming growth factor-ß superfamily ligands and inhibiting signaling through transcription factors Smad 2/3. The goal of this Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ascending dose levels of ACE-536 in healthy volunteers. Thirty-two postmenopausal women were randomized in sequential cohorts of eight subjects each to receive up to two doses of either ACE-536 (0.0625-0.25 mg/kg) or placebo (3:1 randomization) given subcutaneously every 2 weeks. Mean baseline age was 59.4 years, and hemoglobin was 13.2 g/dL. ACE-536 was well tolerated at dose levels up to 0.25 mg/kg over the 1-month treatment period. There were no serious or severe adverse events, nor clinically meaningful changes in safety laboratory measures or vital signs. Mean ACE-536 AUC0-14d and Cmax increased proportionally after first dose; mean t½ was 15-16 days. Dose-dependent increases in hemoglobin concentration were observed, beginning 7 days after initiation of treatment and maintained for several weeks following treatment. The proportion of subjects with a hemoglobin increase ≥1.0 g/dL increased in a dose-dependent manner to 83.3% of subjects in the highest dose group, 0.25 mg/kg. ACE-536 was well tolerated and resulted in sustained increases in hemoglobin levels in healthy postmenopausal women.