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
Authors: Beasley G. , Sanders G. , Zager J. S. , Hochwald S. N. , Grobmyer S. , Andtbacka R. H. , Peterson B. , Peters W. P. , Ross M. I. , Tyler D. S. 
Published: August 2020

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.

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