Evaluation of O6-Benzylguanine-Potentiated Topical Carmustine for Mycosis Fungoides: A Phase 1-2 Clinical Trial

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 through 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 intravenous 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 carmustine and 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 (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 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.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Study Flow Diagram

aPatient had a complete response (CR) on his last study visit prior to his withdrawal because of unresolved grade II skin pain; although maintenance of CR for 4 weeks could not be established, this patient was assigned a response of CR because these were the only available data. AST indicates aspartate aminotransferase; DLCO, diffusing capacity of the lungs for carbon monoxide; PD, progressive disease; PR, partial response; and SD, stable disease.

Figure 2.. Tumor Reduction After O-Benzylguanine Plus Carmustine Treatment Based on the Severity-Weighted Assessment Tool (SWAT) Score

The dashed line represents 50% SWAT score reduction. Patients with a partial response (PR) had 79% to 95% clearance of mycosis fungoides. CR indicates complete response; PD, progressive disease; and SD, stable disease. aThe patient had significant skin inflammation after 3 cycles and withdrew. On clinic follow-up 1 month after withdrawal, a skin biopsy was performed to determine whether the skin changes represented inflammation or persistent cutaneous T-cell lymphoma (CTCL); pathology testing showed no evidence of CTCL, and the patient was assigned a response of SD. bThe patient had a CR on his last study visit before his withdrawal because of unresolved grade II skin pain; although maintenance of CR for 4 weeks could not be established, this patient was assigned a response of CR because these were the only available data.

Figure 3.. Representative Photos of Treatment Results

Red, scaly mycosis fungoides plaques prior to treatment and after 12 cycles of O-benzylguanine plus carmustine on the right medial thigh (A) with complete response (CR) (B), pubic skin (C) with CR (D), and left buttock (E) with partial response (F).