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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Flow diagram of patients enrolled in the trial. Forty-two patients completed the intervention, and 41 patients were available for 3-month follow-up. LPAM, L-phenylalanine mustard.

Fig 2.

Response in patients in this trial (blue) compared with responses seen in a retrospective multicenter study of isolated limb infusion (ILI; gold). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not applicable.

Fig 3.

Time to progression curves for patients in this study (dashed blue line) compared with those treated at Duke University with isolated limb infusion with melphalan (M-ILI) alone (solid gold line). In the present study, the median time to progression was 4.6 months (95% CI, 4.0 to 7.1 months) compared with a median time to progression of 3.2 months (95% CI, 3.1 to 9.9 months) in the previously studied group receiving M-ILI alone.

Fig 4.

Plots of the time between the dose of ADH-1 and melphalan delivery via isolated limb infusion (ILI; in hours) versus the measured plasma concentration of ADH-1 (μg/mL) at the beginning of ILI. As expected, the concentration of ADH-1 decreased as more time elapsed in all patients (r = 0.40). Blue squares represent patients experiencing a complete response (CR) or partial response (PR); gold diamonds represent patients who had progressive disease (PD) or stable disease (SD).

Fig 5.

Gene expression microarray in 10 patients who had two matched biopsies: one obtained just before infusion with ADH-1 on day 1 (pre) and the second just before isolated limb infusion (ILI), approximately 8 hours after day 1 ADH-1 infusion (post). Rows represent patient samples; columns represent genes. Red represents relatively higher expression; green represents relatively lower expression.