Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients
This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinic...
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doaj-c6ef23590d4242b2a6c0d804b3482a412020-11-24T22:00:09ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862017-04-01194255260Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma PatientsArthur E. Frankel0Ugur Eskiocak1Jennifer G. Gill2Stacy Yuan3Vijayashree Ramesh4Thomas W. Froehlich5Chul Ahn6Sean J. Morrison7Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; *Address all correspondence to: NB102.S, Simmons Cancer Center, 2201 Inwood Road, Dallas, TX 75390. Tel.: +1 214 648 1579; fax: +1 214 648 1578.Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; Compass Therapeutics, Cambridge, MAChildren's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TXChildren's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TXChildren's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TXDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TXDepartment of Biostatistics, University of Texas Southwestern Medical Center, Dallas, TXChildren's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TXThis is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy. Key points: Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.http://www.sciencedirect.com/science/article/pii/S1476558617300350 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Arthur E. Frankel Ugur Eskiocak Jennifer G. Gill Stacy Yuan Vijayashree Ramesh Thomas W. Froehlich Chul Ahn Sean J. Morrison |
spellingShingle |
Arthur E. Frankel Ugur Eskiocak Jennifer G. Gill Stacy Yuan Vijayashree Ramesh Thomas W. Froehlich Chul Ahn Sean J. Morrison Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients Neoplasia: An International Journal for Oncology Research |
author_facet |
Arthur E. Frankel Ugur Eskiocak Jennifer G. Gill Stacy Yuan Vijayashree Ramesh Thomas W. Froehlich Chul Ahn Sean J. Morrison |
author_sort |
Arthur E. Frankel |
title |
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients |
title_short |
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients |
title_full |
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients |
title_fullStr |
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients |
title_full_unstemmed |
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients |
title_sort |
digoxin plus trametinib therapy achieves disease control in braf wild-type metastatic melanoma patients |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 |
publishDate |
2017-04-01 |
description |
This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy. Key points: Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients. |
url |
http://www.sciencedirect.com/science/article/pii/S1476558617300350 |
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