title: A phase I study of bortezomib and temozolomide in patients with advanced solid tumors.
abstract: OBJECTIVE
  The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs).
  
  
  METHODS
  Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not.
  
  
  RESULTS
  Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04).
  
  
  CONCLUSIONS
  The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.
authors.affiliation: Department of Medical Oncology, City of Hope, 1500 East Duarte Road, Duarte, CA 91030, USA. jportnow@coh.org
authors.forename: J
authors.initials: J
authors.lastname: Portnow
authors.forename: P
authors.initials: P
authors.lastname: Frankel
authors.forename: S
authors.initials: S
authors.lastname: Koehler
authors.forename: P
authors.initials: P
authors.lastname: Twardowski
authors.forename: S
authors.initials: S
authors.lastname: Shibata
authors.forename: C
authors.initials: C
authors.lastname: Martel
authors.forename: R
authors.initials: R
authors.lastname: Morgan
authors.forename: M
authors.initials: M
authors.lastname: Cristea
authors.forename: W
authors.initials: W
authors.lastname: Chow
authors.forename: D
authors.initials: D
authors.lastname: Lim
authors.forename: V
authors.initials: V
authors.lastname: Chung
authors.forename: K
authors.initials: K
authors.lastname: Reckamp
authors.forename: L
authors.initials: L
authors.lastname: Leong
authors.forename: T W
authors.initials: TW
authors.lastname: Synold
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003606:Dacarbazine; D000077204:Temozolomide