title: Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma.
abstract: OBJECTIVE
  To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O6-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma.
  
  
  METHODS
  Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m2 TMZ or 200 mg/m2 TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment.
  
  
  RESULTS
  One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm.
  
  
  CONCLUSIONS
  The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.
authors.affiliation: Department of Medical Oncology, University of Manchester, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: Damien
authors.initials: D
authors.lastname: Thompson
authors.forename: Jane
authors.initials: J
authors.lastname: Beith
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Andrew
authors.initials: A
authors.lastname: Haydon
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Peter
authors.initials: P
authors.lastname: Mortimer
authors.forename: Peter A
authors.initials: PA
authors.lastname: Harris
authors.forename: Sofia
authors.initials: S
authors.lastname: Baka
authors.forename: Augustus
authors.initials: A
authors.lastname: Seebaran
authors.forename: Ami
authors.initials: A
authors.lastname: Sabharwal
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Watson
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Margison
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D011687:Purines; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D011687:Purines; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C521206:lomeguatrib; D000077204:Temozolomide