Evaluation of o6-benzylguanine?Potentiated topical carmustine formycosis fungoides a phase 1-2 clinical trial

Joselin D. Tacastacas*, Derek V. Chan, Sean Carlson, Stanton L. Gerson, Afshin Dowlati, Pingfu Fu, Kurt Lu, Sarah Groft, Julie Rosenjack, Kord Honda, Thomas S. McCormick, Kevin D. Cooper

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 responsewas 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 20mg of carmustine applied once in combination with 2 daily doses of 120mg/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.

Original languageEnglish (US)
Pages (from-to)413-420
Number of pages8
JournalJAMA dermatology
Volume153
Issue number5
DOIs
StatePublished - May 2017

ASJC Scopus subject areas

  • Dermatology

Fingerprint Dive into the research topics of 'Evaluation of o6-benzylguanine?Potentiated topical carmustine formycosis fungoides a phase 1-2 clinical trial'. Together they form a unique fingerprint.

Cite this