A prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion (M-ILI) in patients with advanced extremity melanoma

Abstract

9025^ Background: ILI with melphalan dosing corrected for ideal body weight (IBW) is a well tolerated treatment for patients with in-transit extremity melanoma with an approximate 30% CR and 44% overall response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. ADH-1 when given systemically in a preclinical model with regional melphalan demonstrated synergistic antitumor activity and had minimal toxicity in a Phase I trial with M-ILI. Methods:AJCC stage IIIB or IIIC extremity melanoma patients were treated with 4000mg of ADH-1 administered systemically on Day 1 and 8 in addition to standard dose M-ILI corrected for IBW on Day 1. Drug pK, and N-cadherin IHC staining were performed on pretreatment tumor from all patients. The primary endpoint was response at 12 weeks determined by modified RECIST. Results: 46 patients were enrolled over 15 months at 4 institutions. Thirty-four patients are presently evaluable for 12 week response. In field responses include 14 CRs (41.2%%), 9 PRs (26.5%), 5 SDs (14.7%), and 6 PDs (17.6%). The OR rate was 67.7% and at a median follow-up of 30 weeks, 8 patients have sustained CRs over 6 months. Of 34 patients, 9 have developed disease outside the region of infusion (median time to progression 12 weeks) at median follow-up 36 weeks. N-cadherin was detected in 20 of 25 (80%) pretreatment tumor samples. Grade IV toxicities included CPK elevation (4), neutropenia (1), acute respiratory distress syndrome (1), pneumonitis (1), and pulmonary infiltrate (1). There were no limb losses or compartment syndromes. Conclusions:This study is not only the first prospective multi-center ILI trial but also the first ILI study to incorporate a targeted agent in an attempt to augment anti-tumor responses. The treatment was well tolerated with CR and OR rates that appear to be significantly improved from standard M-ILI alone. Targeting N-cadherin may represent a novel strategy for improving melanoma sensitivity to chemotherapeutic agents and warrants further investigation in a large randomized multi-center trial. [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .