title: Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours.
abstract: BACKGROUND
  The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine.
  
  
  METHODS
  This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule.
  
  
  RESULTS
  The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease.
  
  
  CONCLUSIONS
  The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates.
authors.affiliation: Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. tawbih@upmc.edu
authors.forename: H A
authors.initials: HA
authors.lastname: Tawbi
authors.forename: L
authors.initials: L
authors.lastname: Villaruz
authors.forename: A
authors.initials: A
authors.lastname: Tarhini
authors.forename: S
authors.initials: S
authors.lastname: Moschos
authors.forename: M
authors.initials: M
authors.lastname: Sulecki
authors.forename: F
authors.initials: F
authors.lastname: Viverette
authors.forename: J
authors.initials: J
authors.lastname: Shipe-Spotloe
authors.forename: R
authors.initials: R
authors.lastname: Radkowski
authors.forename: J M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D011687:Purines / Q000008:administration & dosage*
chemical_list: D011687:Purines; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C521206:lomeguatrib