title: A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma.
abstract: BACKGROUND
  Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed.
  
  
  METHODS
  Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors.
  
  
  RESULTS
  Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n=14) and pain (n=12). Grade 3 toxicities included shortness of breath (n=1), hypertension (n=1), serologic toxicities (n=4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels.
  
  
  CONCLUSIONS
  Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Georgia M
authors.initials: GM
authors.lastname: Beasley
authors.forename: Nicole
authors.initials: N
authors.lastname: McMahon
authors.forename: Gretchen
authors.initials: G
authors.lastname: Sanders
authors.forename: Christina K
authors.initials: CK
authors.lastname: Augustine
authors.forename: Maria A
authors.initials: MA
authors.lastname: Selim
authors.forename: Bercedis
authors.initials: B
authors.lastname: Peterson
authors.forename: Robin
authors.initials: R
authors.lastname: Norris
authors.forename: William P
authors.initials: WP
authors.lastname: Peters
authors.forename: Merrick I
authors.initials: MI
authors.lastname: Ross
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion; D004334:Drug Administration Schedule; D005121:Extremities; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000819:agonists; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000819:agonists; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis
chemical_list: C518575:ADH-1 pepide; D009842:Oligopeptides; D010456:Peptides, Cyclic; D008558:Melphalan