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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
Author(s) -
Beasley Georgia M.,
McMahon Nicole,
Sanders Gretchen,
Augustine Christina K.,
Selim Maria A.,
Peterson Bercedis,
Norris Robin,
Peters William P.,
Ross Merrick I.,
Tyler Douglas S.
Publication year - 2009
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.24509
Subject(s) - medicine , melphalan , tolerability , melanoma , pharmacokinetics , adverse effect , urology , pharmacology , gastroenterology , chemotherapy , anesthesia , surgery , cancer research
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. Cancer 2009. © 2009 American Cancer Society.