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Original Investigation
February 15, 2017

Evaluation of O6-Benzylguanine−Potentiated Topical Carmustine for Mycosis FungoidesA Phase 1-2 Clinical Trial

Author Affiliations
  • 1Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio
  • 2Advanced Dermatology, New Hyde Park, New York
  • 3Cleveland Clinic Imaging Institute, Cleveland, Ohio
  • 4Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio
  • 5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
  • 6Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
  • 7Pathology Department, Case Western Reserve University, Cleveland, Ohio
  • 8Pediatrics Department, Case Western Reserve University, Cleveland, Ohio
JAMA Dermatol. Published online February 15, 2017. doi:10.1001/jamadermatol.2016.5793
Key Points

Question  What is the maximum tolerated dose of topical carmustine in combination with dual dosing of intravenous O6-benzylguanine for the treatment of stage IA through stage IIA cutaneous T-cell lymphoma, mycosis fungoides type?

Findings  In this phase 1-2 clinical trial including 17 patients, the MTD of carmustine was 20 mg applied once, in combination with 2 daily doses of 120 mg/m2 of O6-benzylguanine. The overall clinical response rate was 88% and adverse events were mild.

Meaning  Carmustine in combination with dual-dose O6-benzylguanine is an effective, well-tolerated, skin-directed therapy for early stage cutaneous T-cell lymphoma, mycosis fungoides type.

Abstract

Importance  In a phase 1 trial, single-dose O6-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 O6-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 O6-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 or stage IIA cutaneous T-cell lymphoma, MF type, to evaluate treatment using topical carmustine plus 2 subsequent daily doses of intravenous O6-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 O6-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 O6-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/m2 of O6-benzylguanine. Most adverse events (118 [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 D3 administration.

Conclusions and Relevance  Compared with single-dose O6-benzylguanine and carmustine, dual-dose O6-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 O6-benzylguanine plus carmustine was also ascertained.Trial Registration clinicaltrials.gov Identifier: NCT00961220

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