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: Georgia M Beasley, Nicole McMahon, Gretchen Sanders, Christina K Augustine, Maria A Selim, Bercedis Peterson, Robin Norris, William P Peters, Merrick I Ross, Douglas S Tyler
• Journal: Cancer (Cancer) Vol. 115 Issue 20 Pg. 4766-74 (Oct 15 2009) ISSN: 0008-543X [Print] United States
• PMID: 19637344 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2009 American Cancer Society.

Chemical References

• ADH-1 pepide
• Oligopeptides
• Peptides, Cyclic
• Melphalan

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Chemotherapy, Cancer, Regional Perfusion
• Drug Administration Schedule
• Extremities
• Female
• Humans
• Male
• Melanoma (drug therapy, pathology)
• Melphalan (administration & dosage)
• Oligopeptides (administration & dosage, adverse effects, agonists)
• Peptides, Cyclic (administration & dosage, adverse effects, agonists)
• Skin Neoplasms (drug therapy, pathology)
• Survival Analysis