To evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea] following intravenous O6-benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions.
Open-label, dose-escalation, phase I trial.
Dermatology outpatient clinic and clinical research unit at a university teaching hospital.
A total of 21 adult patients (11 male, 10 female) with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine.
Treatment once every 2 weeks with 120 mg/m2 intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6-alkylguanine-DNA alkyltransferase activity.
Main Outcome Measures
Clinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens.
A minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyl-transferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzyl-guanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P= .02) and inversely with area under the curve of O6-alkylguanine-DNA alkyltransferase over 1 week (P= .01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55–0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug.
O6-benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses.
clinicaltrials.gov Identifier: NCT00003613