title: Phase I clinical trial of O6-benzylguanine and topical carmustine in the treatment of cutaneous T-cell lymphoma, mycosis fungoides type.
abstract: OBJECTIVE
  To evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea] following intravenous O6-benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions.
  
  
  METHODS
  Open-label, dose-escalation, phase I trial.
  
  
  METHODS
  Dermatology outpatient clinic and clinical research unit at a university teaching hospital.
  
  
  METHODS
  A total of 21 adult patients (11 male, 10 female)with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine.
  
  
  METHODS
  Treatment once every 2 weeks with 120 mg/m(2) intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6-alkylguanine-DNA alkyltransferase activity.
  
  
  METHODS
  Clinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens.
  
  
  RESULTS
  A minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyltransferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzylguanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P=.02) and inversely with area under the curve of O6-alkylguanine-DNA alkyltransferase over 1 week (P=.01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55-0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug.
  
  
  CONCLUSIONS
  O6-benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses.
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Narin
authors.initials: N
authors.lastname: Apisarnthanarax
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wood
authors.forename: Seth R
authors.initials: SR
authors.lastname: Stevens
authors.forename: Sean
authors.initials: S
authors.lastname: Carlson
authors.forename: Derek V
authors.initials: DV
authors.lastname: Chan
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.forename: Sarolta K
authors.initials: SK
authors.lastname: Szabo
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Anita C
authors.initials: AC
authors.lastname: Gilliam
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cooper
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism; D001706:Biopsy; D002330:Carmustine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine