Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer
| العنوان: | Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer |
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| المؤلفون: | Carolyn H. Condon, Johanna C. Bendell, Michael S. Gordon, Yijun Yang, Dawn Wilson, Gerard C. Blobe, Suzanne F. Jones, David S. Mendelson, Amelia E. Pearsall, Matthew L. Sherman, Kenneth M. Attie, Ty McClure, Herbert Hurwitz, Sunil Sharma, Neeraj Agarwal |
| المصدر: | Clinical Cancer Research. 20:480-489 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Adult, Male, Cancer Research, Activin Receptors, Type II, Recombinant Fusion Proteins, Peripheral edema, Angiogenesis Inhibitors, Antineoplastic Agents, Pharmacology, Ligands, Pharmacokinetics, Fluorodeoxyglucose F18, Neoplasms, Edema, medicine, Humans, Telangiectasis, Adverse effect, Aged, Neoplasm Staging, Aged, 80 and over, business.industry, Cancer, Middle Aged, medicine.disease, Immunoglobulin Fc Fragments, Angiogenesis inhibitor, Treatment Outcome, Oncology, Tolerability, Positron-Emission Tomography, Pharmacodynamics, Female, medicine.symptom, business |
| الوصف: | Purpose: The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor–like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors. Experimental Design: Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1–4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression. Results: In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients. Conclusion: Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway. Clin Cancer Res; 20(2); 480–9. ©2013 AACR. |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8b742369108c39efee5da6502a570447Test https://doi.org/10.1158/1078-0432.ccr-13-1840Test |
| رقم الانضمام: | edsair.doi.dedup.....8b742369108c39efee5da6502a570447 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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