title: A multicenter phase I dose escalation trial to evaluate safety and tolerability of intra-arterial temozolomide for patients with advanced extremity melanoma using normothermic isolated limb infusion.
abstract: BACKGROUND
  L-phenylalanine mustard (LPAM) has been the standard for use in regional chemotherapy (RC) for unresectable in-transit melanoma. Preclinical data demonstrated that regional temozolomide (TMZ) may be more effective.
  
  
  METHODS
  Patients with AJCC Stage IIIB or IIIC extremity melanoma who failed previous LPAM-based RC were treated with TMZ via isolated limb infusion (ILI) according to a modified accelerated titration design. Drug pharmacokinetic (PK) analysis, tumor gene expression, methylation status of the O6-methylguanine methyltransferase (MGMT) promoter, and MGMT expression were evaluated. Primary objectives were to (1) determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TMZ via ILI and (2) explore biomarker correlates of response.
  
  
  RESULTS
  28 patients completed treatment over 2.5 years at 3 institutions. 19 patients were treated at the MTD defined as 3,200 mg/m(2) [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m(2) level while only grade 1 (n = 15) and grade 2 (n = 4) clinical toxicities occurred at the MTD. At 3-month post-ILI, 10.5 % (2/19) had CR, 5.3 % (1/19) had PR, 15.8 % (3/19) had SD, and 68.4 % (13/19) had PD. Neither PK parameters of TMZ nor MGMT levels were associated with response or toxicity.
  
  
  CONCLUSIONS
  In this first ever use of intra-arterial TMZ in ILI for melanoma, the MTD was determined. While we could not define a marker for TMZ response, the minimal toxicity of TMZ ILI may allow for repeated treatments to increase the response rate as well as clarify the role of MGMT expression.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA, schwe009@mc.duke.edu.
authors.forename: Georgia M
authors.initials: GM
authors.lastname: Beasley
authors.forename: Paul
authors.initials: P
authors.lastname: Speicher
authors.forename: Christina K
authors.initials: CK
authors.lastname: Augustine
authors.forename: Paul C
authors.initials: PC
authors.lastname: Dolber
authors.forename: Bercedis L
authors.initials: BL
authors.lastname: Peterson
authors.forename: Ketan
authors.initials: K
authors.lastname: Sharma
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Mosca
authors.forename: Richard
authors.initials: R
authors.lastname: Royal
authors.forename: Merrick
authors.initials: M
authors.lastname: Ross
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Zager
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015331:Cohort Studies; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005121:Extremities; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077204:Temozolomide; D014018:Tissue Distribution; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide