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/m(2) [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m(2) 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.
Beasley, GM; Speicher, P; Augustine, CK; Dolber, PC; Peterson, BL; Sharma, K; Mosca, PJ; Royal, R; Ross, M; Zager, JS; Tyler, DS
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