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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.

AbstractBACKGROUND:
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.
CONCLUSION:
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.
AuthorsGeorgia M Beasley, Paul Speicher, Christina K Augustine, Paul C Dolber, Bercedis L Peterson, Ketan Sharma, Paul J Mosca, Richard Royal, Merrick Ross, Jonathan S Zager, Douglas S Tyler
JournalAnnals of surgical oncology (Ann Surg Oncol) Vol. 22 Issue 1 Pg. 287-94 (Jan 2015) ISSN: 1534-4681 [Electronic] United States
PMID25145500 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents, Alkylating
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Dacarbazine
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide
Topics
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Alkylating (administration & dosage, pharmacokinetics)
  • Cohort Studies
  • DNA Methylation
  • DNA Modification Methylases (genetics)
  • DNA Repair Enzymes (genetics)
  • Dacarbazine (administration & dosage, analogs & derivatives, pharmacokinetics)
  • Extremities
  • Female
  • Follow-Up Studies
  • Humans
  • Infusions, Intra-Arterial
  • Male
  • Maximum Tolerated Dose
  • Melanoma (drug therapy, genetics, pathology)
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Promoter Regions, Genetic
  • RNA, Messenger (genetics)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin Neoplasms (drug therapy, genetics, pathology)
  • Temozolomide
  • Tissue Distribution
  • Tumor Suppressor Proteins (genetics)

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