title: Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients.
abstract: 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.
  
  
  
  Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: Arthur.frankel@utsouthwestern.edu.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
authors.affiliation: Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; Compass Therapeutics, Cambridge, MA.
authors.forename: Ugur
authors.initials: U
authors.lastname: Eskiocak
authors.affiliation: Children'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, TX.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Gill
authors.affiliation: Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Stacy
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Vijayashree
authors.initials: V
authors.lastname: Ramesh
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Froehlich
authors.affiliation: Department of Biostatistics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Chul
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Children'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, TX.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004077:Digoxin / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D019233:Retreatment; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D004077:Digoxin; D048493:Proto-Oncogene Proteins B-raf