Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma.

Abstract

PURPOSE:

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.

PATIENTS AND 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).

CONCLUSION:

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: Georgia M Beasley, Jonathan C Riboh, Christina K Augustine, Jonathan S Zager, Steven N Hochwald, Stephen R Grobmyer, Bercedis Peterson, Richard Royal, Merrick I Ross, Douglas S Tyler
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 9 Pg. 1210-5 (Mar 20 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 21343562 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• ADH-1 pepide
• Antineoplastic Agents, Alkylating
• Biomarkers, Tumor
• Cadherins
• Oligopeptides
• Peptides, Cyclic
• RNA, Messenger
• Melphalan

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Alkylating (therapeutic use)
• Biomarkers, Tumor (genetics, metabolism)
• Cadherins (antagonists & inhibitors)
• Chemotherapy, Cancer, Regional Perfusion
• Drug Therapy, Combination
• Extremities
• Female
• Gene Expression Profiling
• Humans
• Immunoenzyme Techniques
• Male
• Melanoma (drug therapy, pathology)
• Melphalan (therapeutic use)
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Oligopeptides (therapeutic use)
• Peptides, Cyclic (therapeutic use)
• Prospective Studies
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Skin Neoplasms (drug therapy, pathology)
• Survival Rate
• Treatment Outcome