title: Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma.
abstract: OBJECTIVE
  Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity.
  
  
  METHODS
  Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
  
  
  RESULTS
  In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one).
  
  
  CONCLUSIONS
  To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.
authors.affiliation: Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Georgia M
authors.initials: GM
authors.lastname: Beasley
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Riboh
authors.forename: Christina K
authors.initials: CK
authors.lastname: Augustine
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Zager
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hochwald
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Grobmyer
authors.forename: Bercedis
authors.initials: B
authors.lastname: Peterson
authors.forename: Richard
authors.initials: R
authors.lastname: Royal
authors.forename: Merrick I
authors.initials: MI
authors.lastname: Ross
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000037:antagonists & inhibitors; D010478:Chemotherapy, Cancer, Regional Perfusion; D004359:Drug Therapy, Combination; D005121:Extremities; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008558:Melphalan / Q000627:therapeutic use*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: C518575:ADH-1 pepide; D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D015820:Cadherins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D008558:Melphalan