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Importance In a phase 1 trial, single-dose O 6 -benzylguanine with topical carmustine for patients with early stage (stage IA through stage IIA) cutaneous T-cell lymphoma, mycosis fungoides (MF) type, resulted in clinical responses proportional to inhibition of O 6 -alkylguanine–DNA alkyltransferase activity, but a maximum tolerated dose (MTD) was not reached. Objective To determine whether dose escalation of carmustine in combination with dual-dose O 6 -benzylguanine to prolong alkyltransferase inhibition could reach an MTD. Design, Setting, and Participants A single-arm, phase 1-2 clinical trial conducted at a university teaching hospital enrolled 17 adults with stage IA through stage IIA cutaneous T-cell lymphoma, MF type, to evaluate treatment using topical carmustine plus 2 subsequent daily doses of intravenous O 6 -benzylguanine, administered every 2 weeks for up to 24 weeks (12 cycles). All patients who received treatment were included in an intent-to-treat analysis of the response rate. The study was conducted from February 17, 2010, to April 8, 2014. Data analysis was performed from May 1, 2014, to December 1, 2015. Interventions Topical carmustine and intravenous O 6 -benzylguanine. Main Outcomes and Measures Clinical disease response was assessed by the Severity-Weighted Assessment Tool (score range, 0-400; higher score indicates worse disease). Safety data were acquired by review of adverse events at study visits. Results Of the 17 patients enrolled, 12 (71%) were men; mean (SD) age was 45.2 (14.6) years. There were 7 complete responses and 8 partial responses to combination carmustine and O 6 -benzylguanine treatment. The overall clinical response rate was 88%, with a mean (SD) duration of complete response of 14.43 (6.6) months. The MTD was 20 mg of carmustine applied once in combination with 2 daily doses of 120 mg/m 2 of O 6 -benzylguanine. Most adverse events (112 [67%]) were grade I. Of 15 patients with dermatitis, 5 individuals (33%) demonstrated grade II dermatitis that was unresponsive to topical corticosteroid therapy. The dermatitis was characterized by high levels of macrophage activation, and clearance was associated with vitamin D 3 administration. Conclusions and Relevance Compared with single-dose O 6 -benzylguanine and carmustine, dual-dose O 6 -benzylguanine resulted in higher overall response rates and reduced total carmustine doses but was associated with more cutaneous adverse events. The MTD for dual-dose O 6 -benzylguanine plus carmustine was also ascertained. Trial Registration clinicaltrials.gov Identifier:NCT00961220

Early-stage (IA-IIA) mycosis fungoides (MF) tends to follow a chronic course. Treatment toxic effects are therefore of high consideration, and conservative skin-directed therapies and phototherapy are considered first-line therapies.1–3 Disease relapses are common in MF,4,5 and patients consequently exhaust skin-directed treatment options during their lifetime. Treatment-resistant and refractory cases may then require more aggressive treatments, which incur greater risks of toxic effects.1,3,6,7 An alternative skin-directed therapy for early-stage MF is the topical chemotherapeutic agent carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea] While producing high response rates, depending on the dosage, daily topical carmustine may incur systemic toxic effects not observed in most other skin-directed cutaneous T-cell lymphoma (CTCL) therapies, including myelosuppression and hepatotoxicity.8 Nearly all patients experience cutaneous reactions, including tender erythema, hyperpigmentation, and telangiectasias, which may be treatment limiting. Limiting these adverse effects could make carmustine a more useful therapeutic option for patients with MF. Carmustine damages DNA through chloroethyl alkylation at the O6 site of guanine and subsequent cytotoxic interstrand crosslink formation.9–12 Some malignant diseases have an escape mechanism for nitrosourea resistance via the DNA repair enzyme O6-alkylguanine DNA alkyltransferase (AGT), which covalently transfers the carmustine alkyl adduct to its cysteine residue.9–11,13,14 The novel drug O6-benzylguanine may potentiate carmustine efficacy.15 O6-benzylguanine is a guanine analog and AGT substrate, which transfers its benzyl group to the AGT cysteine residue, thereby irreversibly inactivating AGT and preventing DNA repair.16–20 In tumor cell lines and xenograft models, O6-benzylguanine enhances the sensitivity of malignant diseases to nitrosoureas.21–25 Phase I and II trials have been published on O6-benzylguanine alone and in combination with systemic carmustine in advanced solid tumors, particularly malignant gliomas.26–37 O6-benzylguanine and carmustine together (O6-benzylguanine–carmustine) have never been studied in the treatment of MF, and to our knowledge, topical application of carmustine has not previously been examined in combination with O6-benzylguanine. We conducted a phase I trial of a single topical carmustine administration following intravenous O6-benzylguanine administered once every 2 weeks in the treatment of MF to examine pharmacodynamics of AGT in MF lesions, to determine toxic effects and maximum tolerated dose (MTD), and to follow clinical efficacy measures. Hereinafter, “O6-benzylguanine–carmustine” will refer to the combination of O6-benzylguanine and topical carmustine, unless otherwise specified.