A phase I/II study of systemic ADH-1 in combination with isolated limb infusion with melphalan (ILI-M) in patients (pts) with locally advanced in-transit melanoma
2008; Lippincott Williams & Wilkins; Volume: 26; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2008.26.15_suppl.9013
ISSN1527-7755
AutoresGeorgia M. Beasley, Nicole McMahon, Gretchen Sanders, Patricia A. Zipfel, Christina K. Augustine, William P. Petros, James C. Padussis, M. I. Ross, A. Selim, W. Peters, Douglas S. Tyler,
Tópico(s)Toxin Mechanisms and Immunotoxins
Resumo9013 Background: ILI-M is a well tolerated treatment for pts with in-transit melanoma of the extremity with a 30% CR rate in our own cohort of 50 previously treated pts. ADH-1 is a cyclic pentapeptide that targets N-cadherin adhesion complexes. In a preclinical model of melanoma treatment with ILI-M, the combination of systemic ADH-1 and regional melphalan resulted in a synergistic increase in durable CRs. Methods: A phase I/II study was performed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of systemic ADH-1 in combination with ILI-M in pts with measurable in-transit melanoma of the extremity. The inital phase I study consisted of ADH-1 dose escalation cohorts of 3 pts each at 1.0, 2.0, and 4.0 gm administered systemically on Days 1 (6–8 hr pre ILI-M) and 8 in combination with standard dose ILI-M corrected for ideal body weight. The phase II study expanded the 4.0 gm ADH-1 cohort to 25 pts. N-cadherin IHC staining was performed on pretreatment tumor tissue. Response was defined at 3 months using RECIST criteria. Results: Eleven pts, including 6 previous ILI-M alone failures, have been treated with no observed dose limiting toxicities. Common treatment related grade 1/2 toxicities included pain (n=8), skin/dermatologic (n=11), musculoskeletal (n=4), and nausea (n=4). Grade 3 toxicities included neutropenia (n=1), anemia (n=1), and serologic CPK elevation (n=1). There was 1 Grade 4 CPK elevation. To date, in field responses of the 7 pts followed 3 months post treatment include 4 CRs (57%), 1 SD, and 2 PDs. Interestingly, the 2 pts with PD had tumors that were negative for N-cadherin by IHC. PK analysis demonstrated minimal variability in melphalan plasma levels across pts while ADH-1 plasma concentrations immediately pre-ILI-M increased with each dose cohort (mean=901 ng/mL at 1.0 gm, 1,985 ng/mL at 2.0 gm, and 11,491 ng/mL at 4.0gm.). Conclusions: Systemic ADH-1 administered pre and post ILI-M is a well tolerated, novel targeted therapeutic approach to regionally advanced melanoma. Tumor responses, especially CRs, exceeded expectations in this group of heavily pretreated pts and appear to require N-cadherin expression. Complete accrual to the study is expected by May 2008. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Adherex Technologies Adherex Technologies Adherex Technologies Adherex Technologies
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