A Multicenter Phase I Dose Escalation Trial to Evaluate Safety and Tolerability of Intra-arterial Temozolomide for Patients with Advanced Extremity Melanoma Using Normothermic Isolated Limb Infusion

Background: l-phenylalanine mustard (LPAM) has been the standard for use in regional chemotherapy (RC) for unresectable in-transit melanoma. Preclinical data demonstrated that regional temozolomide (TMZ) may be more effective.

Methods: Patients with AJCC Stage IIIB or IIIC extremity melanoma who failed previous LPAM-based RC were treated with TMZ via isolated limb infusion (ILI) according to a modified accelerated titration design. Drug pharmacokinetic (PK) analysis, tumor gene expression, methylation status of the O₆-methylguanine methyltransferase (MGMT) promoter, and MGMT expression were evaluated. Primary objectives were to (1) determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TMZ via ILI and (2) explore biomarker correlates of response.

Results: 28 patients completed treatment over 2.5 years at 3 institutions. 19 patients were treated at the MTD defined as 3,200 mg/m² [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m² level while only grade 1 (n=15) and grade 2 (n=4) clinical toxicities occurred at the MTD. At 3-month post-ILI, 10.5% (2/19) had CR, 5.3% (1/19) had PR, 15.8% (3/19) had SD, and 68.4% (13/19) had PD. Neither PK parameters of TMZ nor MGMT levels were associated with response or toxicity.

Conclusion: In this first ever use of intra-arterial TMZ in ILI for melanoma, the MTD was determined. While we could not define a marker for TMZ response, the minimal toxicity of TMZ ILI may allow for repeated treatments to increase the response rate as well as clarify the role of MGMT expression.