title: Evaluation of O6-Benzylguanine-Potentiated Topical Carmustine for Mycosis Fungoides: A Phase 1-2 Clinical Trial.
abstract: 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.
  
  
  
  To determine whether dose escalation of carmustine in combination with dual-dose O6-benzylguanine to prolong alkyltransferase inhibition could reach an MTD.
  
  
  
  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.
  
  
  
  Topical carmustine and intravenous O6-benzylguanine.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  clinicaltrials.gov Identifier: NCT00961220.
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio.
authors.forename: Joselin D
authors.initials: JD
authors.lastname: Tacastacas
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio2Advanced Dermatology, New Hyde Park, New York.
authors.forename: Derek V
authors.initials: DV
authors.lastname: Chan
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio3Cleveland Clinic Imaging Institute, Cleveland, Ohio.
authors.forename: Sean
authors.initials: S
authors.lastname: Carlson
authors.affiliation: Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.affiliation: Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Kurt
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio7Pathology Department, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Sarah
authors.initials: S
authors.lastname: Groft
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio8Pediatrics Department, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Julie
authors.initials: J
authors.lastname: Rosenjack
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Kord
authors.initials: K
authors.lastname: Honda
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.affiliation: Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cooper
mesh_terms: D000279:Administration, Cutaneous; D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002330:Carmustine / Q000008:administration & dosage; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006785:Hospitals, University; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine