title: Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: a phase I dose-escalation study.
abstract: BACKGROUND
  Metastatic melanoma (MM) is associated with a high risk of central nervous system (CNS) metastases, and current chemotherapy does not adequately treat or protect patients with MM against CNS metastases. Therefore, the authors initiated a Phase I study to determine the pharmacokinetics and safety profile of temozolomide (TMZ), a novel oral alkylating agent known to cross the blood-brain barrier, in combination with interferon alpha-2b (IFN-alpha2b).
  
  
  METHODS
  Twenty-three patients with MM were enrolled in this single-center, open-label study. Patients with CNS metastasis were excluded. One cohort (n = 6 patients) received oral TMZ (200 mg/m(2) per day) for 5 days every 28-day cycle plus subcutaneous IFN-alpha2b (5 million International Units [MIU]/m(2) per day, 3 times per week). A second cohort (n = 17 patients) received TMZ 150 mg/m(2) per day on the same schedule plus escalating doses of IFN-alpha2b (5.0 MIU/m(2) per day, 7.5 MIU/m(2) per day, and 10 MIU/m(2) per day 3 times per week).
  
  
  RESULTS
  The most common adverse events were fatigue, fever, nausea/emesis, anxiety, and diarrhea. Most toxicity was mild to moderate in severity. The primary dose-limiting toxicity was thrombocytopenia. The maximum tolerated dose was either TMZ 150 mg/m(2) plus IFN-alpha2b 7.5 MIU/m(2) or TMZ 200 mg/m(2) plus IFN-alpha2b 5.0 MIU/m(2). Four patients (17%) had objective responses (one complete response and three partial responses), and four patients had stable disease. The median survival was 9 months. The pharmacokinetics of TMZ were not affected by coadministration of IFN-alpha2b.
  
  
  CONCLUSIONS
  TMZ can be combined safely with IFN-alpha2b. This regimen demonstrated clinical activity in patients with MM and merits further investigation to define its effect on the incidence of brain metastases.
authors.affiliation: Melanoma Center, Cancer Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA. agarwalass@msx.upmc.edu
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D003606:Dacarbazine; D000077204:Temozolomide